IL299510A

IL299510A - Atr inhibitors and uses thereof

Info

Publication number: IL299510A
Application number: IL299510A
Authority: IL
Original assignee: Antengene Discovery Ltd
Priority date: 2020-07-03
Filing date: 2021-07-02
Publication date: 2023-02-01
Also published as: AU2021302146A1; JP2023532303A; CO2023000858A2; EP4175948A1; KR20230035070A; MX2023000198A; CA3185491A1; US20230339927A1; WO2022002245A1; CN116134022A; TW202216701A; BR112022024700A2

Description

WO 2022/002245 PCT/CN2021/104232 ATR INHIBITORS AND USES THEREOF FIELD OF THE DISCLOSURE id="p-1" id="p-1" id="p-1" id="p-1" id="p-1"

[001]The present disclosure generally relates to novel compounds useful as ATR inhibitors, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

BACKGROUND OF THE DISCLOSURE id="p-2" id="p-2" id="p-2" id="p-2" id="p-2"

[002]ATR (also known as FRAP-Related Protein 1; FRP1, MEC1, SCKL, SECKL1) protein kinase is a member of the PI3-Kinase like kinase (PIKK) family of proteins involved in repair and maintenance of the genome and its stability. It is essential to the viability of replicating cells and is activated during S-phase to regulate firing of replication origins and to repair damaged replication forks. Therefore, ATR inhibitors have the potential to be an efficient way in cancer treatment. id="p-3" id="p-3" id="p-3" id="p-3" id="p-3"

[003]While progress has been made for ATR inhibitors, there is still a strong need in the art to develop improved pharmaceutics having inhibitory activity against ATR.

SUMMARY OF THE DISCLOSURE id="p-4" id="p-4" id="p-4" id="p-4" id="p-4"

[004]The present disclosure provides compounds, including stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof, which are capable of inhibiting ATR protein kinase. Methods for use of such compounds for treatment of various diseases or conditions, such as cancer, are also provided. id="p-5" id="p-5" id="p-5" id="p-5" id="p-5"

[005]In one aspect, the present disclosure provides a compound having Formula (I): WO 2022/002245 PCT/CN2021/104232 or a pharmaceutically acceptable salt thereof, wherein Ring Ais absent, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl; Visa direct bond, carbonyl or alkyl optionally substituted with one or more Rc; W and L are each independently a direct bond, -O-, -S-, or -N(Ra)-; R1 is alkyl, cyano, -S(O)2CH3, or S(O)(NH)CH3; R2 is hydrogen, halogen or alkyl optionally substituted with one or more Rb; R5f/H Ring Bis n ; R5 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and haloalkyl; Ra is hydrogen or alkyl; Rb is hydroxyl or halogen; Rc is hydroxyl, halogen or alkyl; n is 0, 1, 2, or 3. id="p-6" id="p-6" id="p-6" id="p-6" id="p-6"

[006]In some embodiments, the present disclosure provides compound having aFormula (II) or Formula (III): WO 2022/002245 PCT/CN2021/104232 (HI). id="p-7" id="p-7" id="p-7" id="p-7" id="p-7"

[007]In some embodiments, the present disclosure provides compound having a formula selected from the group consisting of: (IVb), (IVc), (IVd), WO 2022/002245 PCT/CN2021/104232 (IVe), (IVf), and (IVg), wherein U is O or NH; Visa direct bond, carbonyl or alkyl optionally substituted with one or more Rc; W and L are each independently -N(Ra)-; R1 is alkyl; R2 is hydrogen, halogen or alkyl substituted with one or more Rb; R5 is hydrogen or alkyl; Ra is hydrogen or alkyl; Rb is hydroxyl or halogen; and Rc is hydroxyl, halogen or alkyl.

WO 2022/002245 PCT/CN2021/104232 id="p-8" id="p-8" id="p-8" id="p-8" id="p-8"

[008]In some embodiments, the present disclosure provides compound having Formula (V): or a pharmaceutically acceptable salt thereof, wherein Ring Ais absent, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl; Q is a direct bond or alkyl optionally substituted with one or more Rd; L is -O-, -S-, or -N(Ra)-; R5 vL /NRing Bis M; Ra is hydrogen or alkyl; Rd is hydroxyl, halogen or alkyl; R1 is selected from the group consisting of cyano, hydroxyl, halogen, -S(O)2CH3, and -S(O)(NH)CH3; R5 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and haloalkyl; n is 0, 1, 2, or 3.

WO 2022/002245 PCT/CN2021/104232 id="p-9" id="p-9" id="p-9" id="p-9" id="p-9"

[009]In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. id="p-10" id="p-10" id="p-10" id="p-10" id="p-10"

[0010]In a further aspect, the present disclosure provides a method for treating cancer, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof. id="p-11" id="p-11" id="p-11" id="p-11" id="p-11"

[0011]In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure in the manufacture of a medicament in the prevention or treatment of cancer. id="p-12" id="p-12" id="p-12" id="p-12" id="p-12"

[0012]In a further aspect, the present disclosure provides compounds of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for use in the treatment of cancer. id="p-13" id="p-13" id="p-13" id="p-13" id="p-13"

[0013]In a further aspect, the present disclosure provides a method for inhibiting ATR kinase in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.

DETAILED DESCRIPTION OF THE DISCLOSURE id="p-14" id="p-14" id="p-14" id="p-14" id="p-14"

[0014]Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present disclosure as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described.6 WO 2022/002245 PCT/CN2021/104232 In the event that one or more of the incorporated references and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, the present disclosure controls. All references, patents, patent applications cited in the present disclosure are hereby incorporated by reference in their entireties. id="p-15" id="p-15" id="p-15" id="p-15" id="p-15"

[0015]It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural forms of the same unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

Definitions id="p-16" id="p-16" id="p-16" id="p-16" id="p-16"

[0016]Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2nd Edition, University Science Books, Sausalito, 2006; Smith and March March’s Advanced Organic Chemistry, 6th Edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th Edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference. id="p-17" id="p-17" id="p-17" id="p-17" id="p-17"

[0017]At various places in the present disclosure, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for WO 2022/002245 PCT/CN2021/104232 that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", then it is understood that the "alkyl" represents a linking alkylene group. id="p-18" id="p-18" id="p-18" id="p-18" id="p-18"

[0018]When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. id="p-19" id="p-19" id="p-19" id="p-19" id="p-19"

[0019]When any variable (e.g., R1) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R1 moieties, then the group may optionally be substituted with up to two R1 moieties and R1 at each occurrence is selected independently from the definition of R1. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. id="p-20" id="p-20" id="p-20" id="p-20" id="p-20"

[0020]As used herein, the term "Ci-j" indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i. For examples, C1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms. In some embodiments, the term "C1-12" indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms. id="p-21" id="p-21" id="p-21" id="p-21" id="p-21"

[0021]As used herein, the term "alkyl", whether as part of another term or used independently, refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below. The term "Ci-j alkyl" refers to an alkyl having i to j carbon atoms. In some embodiments, alkyl groups contain 1 to 10 carbon atoms. In some embodiments, alkyl groups contain 1 to 9 carbon atoms. In some embodiments, 8 WO 2022/002245 PCT/CN2021/104232 alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of "Cuio alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of "C1-6 alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1 -butyl, 1-hexyl, 2- hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3- pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like. id="p-22" id="p-22" id="p-22" id="p-22" id="p-22"

[0022]As used herein, the term "alkenyl", whether as part of another term or used independently, refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain carbon atoms. Examples of alkenyl group include, but are not limited to, ethylenyl (or vinyl), propenyl (allyl), butenyl, pentenyl, l-methyl-2 buten-l-yl, 5-hexenyl, and the like. id="p-23" id="p-23" id="p-23" id="p-23" id="p-23"

[0023]As used herein, the term "alkynyl", whether as part of another term or used independently, refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms, to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms. Examples of alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

WO 2022/002245 PCT/CN2021/104232 id="p-24" id="p-24" id="p-24" id="p-24" id="p-24"

[0024]As used herein, the term "cycloalkyl", whether as part of another term or used independently, refer to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms. In some embodiments, the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms. Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1- enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1- cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyl group include, but are not limited to, adamantyl, norbomyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decanyl, bicyclo[ 1,1,!]pentenyl, bicyclo[2,2,l]heptenyl, and the like. id="p-25" id="p-25" id="p-25" id="p-25" id="p-25"

[0025]As used herein, the term "cyano" refers to -CN. id="p-26" id="p-26" id="p-26" id="p-26" id="p-26"

[0026]As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo). id="p-27" id="p-27" id="p-27" id="p-27" id="p-27"

[0027]As used herein, the term "haloalkyl" refers to an alkyl, as defined above, that is substituted by one or more halogens, as defined above. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

WO 2022/002245 PCT/CN2021/104232 id="p-28" id="p-28" id="p-28" id="p-28" id="p-28"

[0028]As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur or phosphorus, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen (including N-oxides). id="p-29" id="p-29" id="p-29" id="p-29" id="p-29"

[0029]As used herein, the term "heteroaryl", whether as part of another term or used independently, refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms. The heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl. The heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Examples of polycyclic heteroaryl include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[l,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. id="p-30" id="p-30" id="p-30" id="p-30" id="p-30"

[0030]As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quatemized form of a basic nitrogen. "Heterocyclyl" also includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclyl radical may be carbon linked or nitrogen linked where such is possible. In some embodiments, the heterocycle is 11 WO 2022/002245 PCT/CN2021/104232 carbon linked. In some embodiments, the heterocycle is nitrogen linked. For example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol- 3-yl (carbon linked). Further, a group derived from imidazole may be imidazol-l-yl (nitrogen linked) or imidazol-3-yl (carbon linked). id="p-31" id="p-31" id="p-31" id="p-31" id="p-31"

[0031]In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The fused, spiro and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyl include, but are not limited to oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.Examples of fused heterocyclyl include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[l,2-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, [l,2,3]triazolo[4,3-a]pyridinyl groups, and the like. Examples of spiro heterocyclyl include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of bridged heterocyclyl include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo[3.1.0]hexane, 8-aza- bicyclo[3.2.!]octane, l-aza-bicyclo[2.2.2]octane, l,4-diazabicyclo[2.2.2]octane (DABCO), and the like. id="p-32" id="p-32" id="p-32" id="p-32" id="p-32"

[0032]As used herein, the term "hydroxyl" refers to -OH. id="p-33" id="p-33" id="p-33" id="p-33" id="p-33"

[0033]As used herein, the term "partially unsaturated" refers to a radical that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

WO 2022/002245 PCT/CN2021/104232 id="p-34" id="p-34" id="p-34" id="p-34" id="p-34"

[0034]As used herein, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted", references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

Compounds id="p-35" id="p-35" id="p-35" id="p-35" id="p-35"

[0035]The present disclosure provides novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the disclosed compounds. id="p-36" id="p-36" id="p-36" id="p-36" id="p-36"

[0036]In one aspect, the present disclosure provides a compound having Formula (I): R2 (I) or a pharmaceutically acceptable salt thereof, wherein 13 WO 2022/002245 PCT/CN2021/104232 Ring Ais absent, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl; Visa direct bond, carbonyl or alkyl optionally substituted with one or more Rc; W and L are each independently a direct bond, -O-, -S-, or -N(Ra)-; R1 is alkyl, cyano, -S(O)2CH3, or-S(O)(NH)CH3; R2 is hydrogen, halogen or alkyl optionally substituted with one or more Rb; R5 R5 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and haloalkyl; Ra is hydrogen or alkyl; Rb is hydroxyl or halogen; Rc is hydroxyl, halogen or alkyl; n is 0, 1, 2, or 3. id="p-37" id="p-37" id="p-37" id="p-37" id="p-37"

[0037]In some embodiments, Visa direct bond. id="p-38" id="p-38" id="p-38" id="p-38" id="p-38"

[0038]In some embodiments, V is carbonyl. id="p-39" id="p-39" id="p-39" id="p-39" id="p-39"

[0039]In some embodiments, V is alkyl optionally substituted with one or more Rc.In certain embodiments, V is C1-6alkyl, C1-5alkyl, C1-4alkyl or C1-3alkyl. id="p-40" id="p-40" id="p-40" id="p-40" id="p-40"

[0040]In some embodiments, Ring A is absent. id="p-41" id="p-41" id="p-41" id="p-41" id="p-41"

[0041]In some embodiments, Ring Ais 3- to 6-membered cycloalkyl id="p-42" id="p-42" id="p-42" id="p-42" id="p-42"

[0042]In certain embodiments, Ring A is cyclopropyl. In certain embodiments, Ring A is WO 2022/002245 PCT/CN2021/104232 id="p-43" id="p-43" id="p-43" id="p-43" id="p-43"

[0043]In certain embodiments, Ring A is cyclopentyl. In certain embodiments, Ring A is id="p-44" id="p-44" id="p-44" id="p-44" id="p-44"

[0044]In certain embodiments, Ring A is cyclohexyl. In certain embodimens, Ring A is id="p-45" id="p-45" id="p-45" id="p-45" id="p-45"

[0045]In some embodiments, Ring Ais 5- to 6-membered heterocyclyl. id="p-46" id="p-46" id="p-46" id="p-46" id="p-46"

[0046]In certain embodiments, Ring Ais 5-membered heterocyclyl containing at least one nitrogen atom. In certain embodiments, Ring A is 5-membered heterocyclyl containing at least two nitrogen atoms. In certain embodiments, Ring A is 5-membered heterocyclyl containing two nitrogen atoms. id="p-47" id="p-47" id="p-47" id="p-47" id="p-47"

[0047]In some embodiments, Ring Ais pyrazolyl. id="p-48" id="p-48" id="p-48" id="p-48" id="p-48"

[0048]In certain embodiments, Ring Ais 6-membered heterocyclyl. id="p-49" id="p-49" id="p-49" id="p-49" id="p-49"

[0049]In some embodiments, Ring A is tetrahydropyranyl. id="p-50" id="p-50" id="p-50" id="p-50" id="p-50"

[0050]In some embodiments, Ring Ais 5- to 6-membered heteroaryl. id="p-51" id="p-51" id="p-51" id="p-51" id="p-51"

[0051]In certain embodiments, Ring Ais 5- to 6-membered heteroaryl containing at least one nitrogen atom. id="p-52" id="p-52" id="p-52" id="p-52" id="p-52"

[0052]In certain embodiments, Ring A is 5-membered heteroaryl containing at least one nitrogen atom. In certain embodiments, Ring A is 5-membered heteroaryl containing at least one nitrogen atom and additional heteroatom(s) selected from O,N or S. In certain embodiments, Ring A is thiazolyl, triazolyl or isoxazolyl. id="p-53" id="p-53" id="p-53" id="p-53" id="p-53"

[0053]In certain embodiments, Ring Ais 6-membered heteroaryl containing at least one nitrogen atom. In certain embodiments, Ring A is 6-membered heteroaryl containing at least one nitrogen atom and additional heteroatom(s) selected from O, N or S. In certain embodiments, Ring A is pyridyl.15 WO 2022/002245 PCT/CN2021/104232 id="p-54" id="p-54" id="p-54" id="p-54" id="p-54"

[0054]In some embodiments, W is a direct bond. id="p-55" id="p-55" id="p-55" id="p-55" id="p-55"

[0055]In some embodiments, W is -N(Ra)-. id="p-56" id="p-56" id="p-56" id="p-56" id="p-56"

[0056]In certain embodiments, W is -N(Ra)-, and Ra is hydrogen. id="p-57" id="p-57" id="p-57" id="p-57" id="p-57"

[0057]In certain embodiments, W is -N(Ra)-, and Ra is alkyl. In certain embodiments, W is -N(Ra)-, and Ra is C1-3 alkyl. In certain embodiments, W is - N(Ra)-, and Ra is methyl. id="p-58" id="p-58" id="p-58" id="p-58" id="p-58"

[0058]In some embodiments, Ring Ais 3- to 6-membered cycloalkyl, 5- to 6- membered heterocyclyl or 5- to 6-membered heteroaryl, and W is a direct bond. id="p-59" id="p-59" id="p-59" id="p-59" id="p-59"

[0059]In some embodiments, Ring A is absent, and W is -N(Ra)-. id="p-60" id="p-60" id="p-60" id="p-60" id="p-60"

[0060]In some embodiments, Ring Ais absent, W is -N(Ra)-, and Ra is hydrogen. id="p-61" id="p-61" id="p-61" id="p-61" id="p-61"

[0061]In certain embodiments, Ring A is absent, W is -N(Ra)-, and Ra is alkyl. In certain embodiments, Ring A is absent, W is -N(Ra)-, and Ra is C1-3 alkyl. In certain embodiments, Ring Ais absent, W is -N(Ra)-, and Ra is methyl. id="p-62" id="p-62" id="p-62" id="p-62" id="p-62"

[0062]In some embodiments, Ring Ais absent, and W is a direct bond. id="p-63" id="p-63" id="p-63" id="p-63" id="p-63"

[0063]In some embodiments, R1 is alkyl. id="p-64" id="p-64" id="p-64" id="p-64" id="p-64"

[0064]In some embodiments, R1 is C1-3 alkyl. id="p-65" id="p-65" id="p-65" id="p-65" id="p-65"

[0065]In some embodiments, R1 is cyano. id="p-66" id="p-66" id="p-66" id="p-66" id="p-66"

[0066]In some embodiments, R1 is hydroxyl. id="p-67" id="p-67" id="p-67" id="p-67" id="p-67"

[0067]In some embodiments, R1 is -S(O)2CH3. id="p-68" id="p-68" id="p-68" id="p-68" id="p-68"

[0068]In some embodiments, R1 is -S(O)(NH)CH3. id="p-69" id="p-69" id="p-69" id="p-69" id="p-69"

[0069]In some embodiments, Ring Ais absent, and R1 is cyano or -S(O)2CH3.

WO 2022/002245 PCT/CN2021/104232 id="p-70" id="p-70" id="p-70" id="p-70" id="p-70"

[0070]In some embodiments, Ring Ais 3- to 6-membered cycloalkyl, 5- to 6- membered heterocyclyl or 5- to 6-membered heteroaryl, and R1 is alkyl, hydroxyl, - S(O)2CH3 or-S(O)(NH)CH3. id="p-71" id="p-71" id="p-71" id="p-71" id="p-71"

[0071]In some embodiments, Ring Ais cyclopropyl, cyclohexyl, tetrahydropyranyl, thiazolyl, pyridyl or isoxazolyl, and R1 is -S(O)2CH3 or -S(O)(NH)CH3. id="p-72" id="p-72" id="p-72" id="p-72" id="p-72"

[0072]In some embodiments, Ring A is cyclopropyl, R1 is -S(O)2CH3 or - S(O)(NH)CH3. In some embodiments, Ring A isS(O)(NH)CH3., R1 is-S(O)2CH3 or- id="p-73" id="p-73" id="p-73" id="p-73" id="p-73"

[0073]In certain embodiments, Ring A is cyclopropyl, R1 is -S(O)2CH3 or - S(O)(NH)CH3, and nisi. In certain embodiments, Ring A is S(O)2CH3 or-S(O)(NH)CH3, and n is 1., R1 is - id="p-74" id="p-74" id="p-74" id="p-74" id="p-74"

[0074]In certain embodiments, Ring Ais cyclopropyl, W is a direct bond, R1 is - S(O)2CH3 or -S(O)(NH)CH3, and nisi. In certain embodiments, Ring A is , W is a direct bond, R1 is -S(O)2CH3 or -S(O)(NH)CH3, and n is 1. id="p-75" id="p-75" id="p-75" id="p-75" id="p-75"

[0075] Ox /O ST . (R1)n־W-M-^- . X >In some embodiments, — is or HN. ZO id="p-76" id="p-76" id="p-76" id="p-76" id="p-76"

[0076] In some embodiments, Ring A is cyclopentyl, and R1 is cyano. In certain embodiments, Ring Ais , and R1 is cyano. In certain embodiments, Ring A is , R1 is cyano, and nisi.

WO 2022/002245 PCT/CN2021/104232 id="p-77" id="p-77" id="p-77" id="p-77" id="p-77"

[0077] In certain embodiments, Ring A is cyclopentyl, W is a direct bond, R1 is cyano, and n is 1. In certain embodiments, Ring Ais , W is a direct bond, R1is cyano, and n is 1. id="p-78" id="p-78" id="p-78" id="p-78" id="p-78"

[0078] In some embodiments,. ־ AJ4 ؛ R1)n-W )is id="p-79" id="p-79" id="p-79" id="p-79" id="p-79"

[0079] In some embodiments, Ring A is cyclohexyl, and R1 is cyano. In certain embodiments, Ring Ais and R1 is cyano. In certain embodiments, Ring Ais 1 is cyano, and n is 1. id="p-80" id="p-80" id="p-80" id="p-80" id="p-80"

[0080] In certain embodiments, Ring A is cyclopentyl, W is a direct bond, R1 is cyano, and n is 1. In certain embodiments, Ring Ais , W is a direct bond, R1is cyano, and n is 1. id="p-81" id="p-81" id="p-81" id="p-81" id="p-81"

[0081] In some embodiments,(R1)n־W-M-^- .is id="p-82" id="p-82" id="p-82" id="p-82" id="p-82"

[0082] In some embodiments, Ring Ais 5-membered heterocyclyl, and R1 is alkyl. id="p-83" id="p-83" id="p-83" id="p-83" id="p-83"

[0083] In some embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, and R1 is C1-3 alkyl. id="p-84" id="p-84" id="p-84" id="p-84" id="p-84"

[0084] In some embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, and R1 is methyl. In certain embodiments, Ring Ais pyrazolyl, isoxazolyl or triazolyl, R1 is methyl, and n is 2.

WO 2022/002245 PCT/CN2021/104232 id="p-85" id="p-85" id="p-85" id="p-85" id="p-85"

[0085]In some embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, W is a direct bond, and R1 is methyl. In certain embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, W is a direct bond, R1 is methyl, and n is 2. id="p-86" id="p-86" id="p-86" id="p-86" id="p-86"

[0086]In some embodiments, —y is N A or id="p-87" id="p-87" id="p-87" id="p-87" id="p-87"

[0087]In some embodiments, Ring Ais 5- to 6-membered heteroaryl, and R1 is - S(O)2CH3. id="p-88" id="p-88" id="p-88" id="p-88" id="p-88"

[0088]In certain embodiments, Ring Ais thiazolyl or pyridyl, and R1 is -S(O)2CH3. In certain embodiments, Ring Ais thiazolyl or pyridyl, R1 is -S(O)2CH3, and n is 1. id="p-89" id="p-89" id="p-89" id="p-89" id="p-89"

[0089]In certain embodiments, Ring Ais thiazolyl or pyridyl, W is a direct bond, and R1 is -S(O)2CH3. In certain embodiments, Ring A is thiazolyl or pyridyl, W is a direct bond, R1 is -S(O)2CH3, and n is 1. id="p-90" id="p-90" id="p-90" id="p-90" id="p-90"

[0090] In some embodiments, or(R1)n־W-M-^- id="p-91" id="p-91" id="p-91" id="p-91" id="p-91"

[0091]In some embodiments, Lisa bond. id="p-92" id="p-92" id="p-92" id="p-92" id="p-92"

[0092]In some embodiments, L is -O-. id="p-93" id="p-93" id="p-93" id="p-93" id="p-93"

[0093]In some embodiments, L is -S-. id="p-94" id="p-94" id="p-94" id="p-94" id="p-94"

[0094]In some embodiments, L is -N(Ra)-. id="p-95" id="p-95" id="p-95" id="p-95" id="p-95"

[0095]In certain embodiments, Ra is hydrogen. id="p-96" id="p-96" id="p-96" id="p-96" id="p-96"

[0096]In certain embodiments, Ra is C1-3 alkyl. id="p-97" id="p-97" id="p-97" id="p-97" id="p-97"

[0097] In some embodiments, Ring B is R5 WO 2022/002245 PCT/CN2021/104232 id="p-98" id="p-98" id="p-98" id="p-98" id="p-98"

[0098] In some embodiments, L is -O-, -S- or -N(Ra)-, and Ring B is Rs id="p-99" id="p-99" id="p-99" id="p-99" id="p-99"

[0099] In certain embodiments, L is -O-, and Ring B is id="p-100" id="p-100" id="p-100" id="p-100" id="p-100"

[00100]In certain embodiments, L is -S-, and Ring B is R5 A [00101]In certain embodiments, L is -N(Ra)-, Ra is hydrogen, and Ring Bis N id="p-102" id="p-102" id="p-102" id="p-102" id="p-102"

[00102]In certain embodiments, L is -N(Ra)-, Ra is hydrogen, and Ring B is id="p-103" id="p-103" id="p-103" id="p-103" id="p-103"

[00103]In some embodiments, R2 is hydrogen. id="p-104" id="p-104" id="p-104" id="p-104" id="p-104"

[00104]In some embodiments, R2 is halogen. In certain embodiments, R2 is fluoro, chloro or bromo. In certain embodiments, R2 is fluoro. id="p-105" id="p-105" id="p-105" id="p-105" id="p-105"

[00105]In some embodiments, R2 is alkyl substituted with one or more Rb. In certain embodiments, R2 is Cn3 alkyl substituted with one or more Rb. id="p-106" id="p-106" id="p-106" id="p-106" id="p-106"

[00106]In some embodiments, R2 is alkyl substituted with one or more Rb, and Rb is hydroxyl or fluoro. In certain embodiments, R2 is C1-3 alkyl substituted with one or more Rb, and Rb is hydroxyl or fluoro. id="p-107" id="p-107" id="p-107" id="p-107" id="p-107"

[00107]In some embodiments, R2 is -CHOH or CHF.

WO 2022/002245 PCT/CN2021/104232 id="p-108" id="p-108" id="p-108" id="p-108" id="p-108"

[00108]In some embodiments, the present disclosure provides compound having a Formula (II) or Formula (III): (HI) wherein V, W, L, Ring A, Ring B, R1 and R2 are as defined supra. id="p-109" id="p-109" id="p-109" id="p-109" id="p-109"

[00109]In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of: (IVb), (IVc), WO 2022/002245 PCT/CN2021/104232 (IVd), (IVe), or a pharmaceutically acceptable salt thereof, wherein U is O or NH; Visa direct bond, carbonyl or alkyl optionally substituted with one or more Rc; W and L are each independently -O-, -S- or -N(Ra)-; R1 is alkyl; R2 is hydrogen, halogen or alkyl substituted with one or more Rb;22 WO 2022/002245 PCT/CN2021/104232 R3 is halogen; R5 is hydrogen or alkyl; Ra is hydrogen or alkyl; Rb is hydroxyl or halogen; and Rc is hydroxyl, halogen or alkyl. id="p-110" id="p-110" id="p-110" id="p-110" id="p-110"

[00110]In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of.

WO 2022/002245 PCT/CN2021/104232 WO 2022/002245 PCT/CN2021/104232 or a pharmaceutically acceptable salt thereof. id="p-111" id="p-111" id="p-111" id="p-111" id="p-111"

[00111]In a further aspect, the present disclosure provides a compound having Formula (V): or a pharmaceutically acceptable salt thereof, wherein Ring Ais absent, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl;25 WO 2022/002245 PCT/CN2021/104232 Qis a direct bond or alkyl optionally substituted with one or more Rd; L is -O-, -S-or -N(Ra)-; R5 ׳NRing Bis M; Rd is hydrogen or alkyl; Rd is hydroxyl, halogen or alkyl; R1 is selected from the group consisting of cyano, hydroxyl, halogen, -S(O)2CH3, and -S(O)(NH)CH3; R5 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and haloalkyl; n is 0, 1, 2, or 3. id="p-112" id="p-112" id="p-112" id="p-112" id="p-112"

[00112]In some embodiments, Q is a direct bond. id="p-113" id="p-113" id="p-113" id="p-113" id="p-113"

[00113]In some embodiments, Qis alkyl. In certain embodiments, Qis C1-6alkyl, C1-5 alkyl, C1-4 alkyl or C1-3 alkyl. id="p-114" id="p-114" id="p-114" id="p-114" id="p-114"

[00114]In some embodiments, Ring A is 3- to 6-membered cycloalkyl. In certain embodiments, Ring Ais cyclopropyl. In certain embodiments, Ring A is . id="p-115" id="p-115" id="p-115" id="p-115" id="p-115"

[00115]In some embodiments, Ring A is absent. id="p-116" id="p-116" id="p-116" id="p-116" id="p-116"

[00116]In some embodiments, Ring A is 5- to 6-membered heterocyclyl. In certain embodiments, Ring Ais tetrahydropyranyl. In certain embodiments, Ring A is WO 2022/002245 PCT/CN2021/104232 id="p-117" id="p-117" id="p-117" id="p-117" id="p-117"

[00117]In some embodiments, Q is alkyl and Ring Ais absent. id="p-118" id="p-118" id="p-118" id="p-118" id="p-118"

[00118]In some embodiments, Q is a direct bond and Ring Ais 3- to 6-membered cycloalkyl or 5- to 6-membered heterocyclyl. id="p-119" id="p-119" id="p-119" id="p-119" id="p-119"

[00119]In some embodiments, R1 is -S(O)2CH3 or-S(O)(NH)CH3. id="p-120" id="p-120" id="p-120" id="p-120" id="p-120"

[00120]In some embodiments, R1 is cyano, hydroxyl or halogen. id="p-121" id="p-121" id="p-121" id="p-121" id="p-121"

[00121]In some embodiments, Ring Ais absent, 3- to 6-membered cycloalkyl or 5- to 6-membered heterocyclyl, and R1 is -S(O)2CH3 or-S(O)(NH)CH3. id="p-122" id="p-122" id="p-122" id="p-122" id="p-122"

[00122]In some embodiments, Ring Ais absent or 3- to 6-membered cycloalkyl, andR1 is cyano, hydroxyl or halogen. id="p-123" id="p-123" id="p-123" id="p-123" id="p-123"

[00123]In some embodiments, L is -O-. id="p-124" id="p-124" id="p-124" id="p-124" id="p-124"

[00124]In some embodiments, L is -S-. id="p-125" id="p-125" id="p-125" id="p-125" id="p-125"

[00125]In some embodiments, L is -N(Ra)- and Ra is hydrogen. id="p-126" id="p-126" id="p-126" id="p-126" id="p-126"

[00126]In some embodiments, Ring Bis PI . id="p-127" id="p-127" id="p-127" id="p-127" id="p-127"

[00127]In some embodiments, R5 is hydrogen or alkyl. id="p-128" id="p-128" id="p-128" id="p-128" id="p-128"

[00128]In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of: WO 2022/002245 PCT/CN2021/104232 or a pharmaceutically acceptable salt thereof. id="p-129" id="p-129" id="p-129" id="p-129" id="p-129"

[00129]Exemplary compounds of the present disclosure are set forth in Table below Table 128 WO 2022/002245 PCT/CN2021/104232 Compound No. Compound structure 1a VJIjl JOn 2a - 2CM N 3a Mw 4a C n-nx a o z 6a ovof A x 2s N N N O z °S z )to X oz 29 WO 2022/002245 PCT/CN2021/104232 WO 2022/002245 PCT/CN2021/104232 15a A N OH 16a ב כ ־ ־ P " // —( pA P O Z — o x / ]ילסo z 18a V> Im Pn 'F 19a o ' J ، - 21a MC N'Nx 1 WO 2022/002245 PCT/CN2021/104232 WO 2022/002245 PCT/CN2021/104232 29a 30x 31a 32a V fS jA 33a MA 34a %z°JO1 X^n XTrti 35a mxnA WO 2022/002245 PCT/CN2021/104232 WO 2022/002245 PCT/CN2021/104232 id="p-130" id="p-130" id="p-130" id="p-130" id="p-130"

[00130]Compounds provided herein are described with reference to both generic formulae and specific compounds. In addition, the compounds of the present disclosure may exist in a number of different forms or derivatives, including but not 35 WO 2022/002245 PCT/CN2021/104232 limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts, all within the scope of the present disclosure. id="p-131" id="p-131" id="p-131" id="p-131" id="p-131"

[00131]As used herein, the term "prodrugs" refers to compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety. id="p-132" id="p-132" id="p-132" id="p-132" id="p-132"

[00132]As used herein, the term "soft drug" refers to compounds that exert a pharmacological effect but break down to inactive metabolites degradants so that the activity is of limited time. See, for example, "Soft drugs: Principles and methods for the design of safe drugs", Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449-469, 1984, which is hereby incorporated by reference in its entirety. id="p-133" id="p-133" id="p-133" id="p-133" id="p-133"

[00133]As used herein, the term "metabolite", e.g., active metabolite overlaps with prodrug as described above. Thus, such metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject. For example, such metabolites may result from oxidation, reduction, WO 2022/002245 PCT/CN2021/104232 hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodmg. Of these, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or of lower activity than the metabolic product. For active metabolites, the parent compound may be either an active compound or may be an inactive prodrug. id="p-134" id="p-134" id="p-134" id="p-134" id="p-134"

[00134]Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem 40:2011-2016; Shan et al., JPharm Sci 86:756-757; Bagshawe, 1995, DrugDevRes 34:220-230; Wermuth, supra. id="p-135" id="p-135" id="p-135" id="p-135" id="p-135"

[00135]As used herein, the term "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith. id="p-136" id="p-136" id="p-136" id="p-136" id="p-136"

[00136]As used herein, the term "pharmaceutically acceptable salt", unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug. id="p-137" id="p-137" id="p-137" id="p-137" id="p-137"

[00137]Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, 37 WO 2022/002245 PCT/CN2021/104232 malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid. id="p-138" id="p-138" id="p-138" id="p-138" id="p-138"

[00138]Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remington's Pharmaceutical Sciences, l^ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases. id="p-139" id="p-139" id="p-139" id="p-139" id="p-139"

[00139]Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. id="p-140" id="p-140" id="p-140" id="p-140" id="p-140"

[00140]Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, WO 2022/002245 PCT/CN2021/104232 morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. id="p-141" id="p-141" id="p-141" id="p-141" id="p-141"

[00141]It is also to be understood that the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystal or polymorphic forms), and the present disclosure is intended to encompass all such forms. id="p-142" id="p-142" id="p-142" id="p-142" id="p-142"

[00142]As used herein, the term "solvate" or "solvated form" refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. id="p-143" id="p-143" id="p-143" id="p-143" id="p-143"

[00143]As used herein, the terms "crystal form", "crystalline form", "polymorphic forms" and "polymorphs" can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions. id="p-144" id="p-144" id="p-144" id="p-144" id="p-144"

[00144]The compounds of present disclosure can comprise one or more asymmetric centers depending on substituent selection, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds provided herein may have an asymmetric carbon center, and thus compounds provided herein may have either the (R) or (S) stereo-configuration at a 39 WO 2022/002245 PCT/CN2021/104232 carbon asymmetric center. Therefore, compounds of the present disclosure may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. id="p-145" id="p-145" id="p-145" id="p-145" id="p-145"

[00145]As used herein, the term "enantiomer" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. The term "diastereomer" refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. id="p-146" id="p-146" id="p-146" id="p-146" id="p-146"

[00146]Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the opposite enantiomer, and may also be referred to as "optically enriched". "Optically enriched", as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound provided herein or it can be done on a final racemic product. Absolute stereochemistry may be determined by X- ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, absolute stereochemistry may be determined by Vibrational Circular Dichroism (VCD) spectroscopy analysis. See, for example, Jacques, et ah, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et ah, Tetrahedron 33:2725 (1977); Eliel, E.L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).

WO 2022/002245 PCT/CN2021/104232 id="p-147" id="p-147" id="p-147" id="p-147" id="p-147"

[00147]In some embodiments, mixtures of diastereomers, for example mixtures of diastereomers enriched with 51% or more of one of the diastereomers, including for example 60% or more, 70% or more, 80% or more, or 90% or more of one of the diastereomers are provided. id="p-148" id="p-148" id="p-148" id="p-148" id="p-148"

[00148]In some embodiments, compounds provided herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The present disclosure additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers. id="p-149" id="p-149" id="p-149" id="p-149" id="p-149"

[00149]The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine- enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system (for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole). Valence tautomers include interconversions by reorganization of some of the bonding electrons Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. id="p-150" id="p-150" id="p-150" id="p-150" id="p-150"

[00150]The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to 1H, 2H, 3H, nC, 12c, 13C, 14c, 14N, ISN, 160, 170, 18o, 31P, 32p, 32s, 33S, 34S, 36S, 17F, 18F, 19F, 35Cl, 37Cl, 79Br, 8IBr, 124I, 127I and 131I. In some embodiments, WO 2022/002245 PCT/CN2021/104232 hydrogen includes protium, deuterium and tritium. In some embodiments, carbon includes L2C and 13c.

Synthesis of compounds id="p-151" id="p-151" id="p-151" id="p-151" id="p-151"

[00151]Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the Schemes are for better illustration and can be changed as appropriate. The embodiments of the compounds in examples were synthesized for the purposes of research and potentially submission to regulatory agencies. id="p-152" id="p-152" id="p-152" id="p-152" id="p-152"

[00152]The reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by one skilled in the art. id="p-153" id="p-153" id="p-153" id="p-153" id="p-153"

[00153]Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T W Greene and P G M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.

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[00154]Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.H or 13C), infrared spectroscopy, spectrophotometry (e.g. UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety), and normal phase silica chromatography. id="p-155" id="p-155" id="p-155" id="p-155" id="p-155"

[00155]The known starting materials of the present disclosure can be synthesized by using or according to the known methods in the art, or can be purchased from commercial suppliers. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification. id="p-156" id="p-156" id="p-156" id="p-156" id="p-156"

[00156]Unless otherwise specified, the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. id="p-157" id="p-157" id="p-157" id="p-157" id="p-157"

[00157]For illustrative purposes, the Examples section below shows synthetic route for preparing the compounds of the present disclosure as well as key intermediates. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

Pharmaceutical Compositions WO 2022/002245 PCT/CN2021/104232 id="p-158" id="p-158" id="p-158" id="p-158" id="p-158"

[00158]In a further aspect, there is provided pharmaceutical compositions comprising one or more molecules or compounds of the present disclosure, or a pharmaceutically acceptable salt thereof. id="p-159" id="p-159" id="p-159" id="p-159" id="p-159"

[00159]In another aspect, there is provided pharmaceutical composition comprising one or more molecules or compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient. id="p-160" id="p-160" id="p-160" id="p-160" id="p-160"

[00160]As used herein, the term "pharmaceutical composition" refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject. id="p-161" id="p-161" id="p-161" id="p-161" id="p-161"

[00161]As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used herein includes both one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent". id="p-162" id="p-162" id="p-162" id="p-162" id="p-162"

[00162]The particular excipient used will depend upon the means and purpose for which the compounds of the present disclosure is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans. In general, safe solvents are non- toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. id="p-163" id="p-163" id="p-163" id="p-163" id="p-163"

[00163]In some embodiments, suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than 44 WO 2022/002245 PCT/CN2021/104232 about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICSIM or polyethylene glycol (PEG). id="p-164" id="p-164" id="p-164" id="p-164" id="p-164"

[00164]In some embodiments, suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. id="p-165" id="p-165" id="p-165" id="p-165" id="p-165"

[00165]The pharmaceutical compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.

WO 2022/002245 PCT/CN2021/104232 id="p-166" id="p-166" id="p-166" id="p-166" id="p-166"

[00166]A variety of routes are contemplated for the pharmaceutical compositions provided herein, and accordingly the pharmaceutical composition provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable as liquid dosage forms, and a powder suitable for reconstitution with an appropriate solution as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage form. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form. id="p-167" id="p-167" id="p-167" id="p-167" id="p-167"

[00167]The quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved. As used herein, the term "therapeutically effective amount" refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. id="p-168" id="p-168" id="p-168" id="p-168" id="p-168"

[00168]In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for oral administration. id="p-169" id="p-169" id="p-169" id="p-169" id="p-169"

[00169]In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Suitable pharmaceutically- WO 2022/002245 PCT/CN2021/104232 acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as com starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art. id="p-170" id="p-170" id="p-170" id="p-170" id="p-170"

[00170]In certain embodiments, the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. id="p-171" id="p-171" id="p-171" id="p-171" id="p-171"

[00171]In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).

WO 2022/002245 PCT/CN2021/104232 id="p-172" id="p-172" id="p-172" id="p-172" id="p-172"

[00172]In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. id="p-173" id="p-173" id="p-173" id="p-173" id="p-173"

[00173]In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. id="p-174" id="p-174" id="p-174" id="p-174" id="p-174"

[00174]In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent. id="p-175" id="p-175" id="p-175" id="p-175" id="p-175"

[00175]In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for injection administration. id="p-176" id="p-176" id="p-176" id="p-176" id="p-176"

[00176]In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or 48 WO 2022/002245 PCT/CN2021/104232 prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. id="p-177" id="p-177" id="p-177" id="p-177" id="p-177"

[00177]In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for inhalation administration. id="p-178" id="p-178" id="p-178" id="p-178" id="p-178"

[00178]In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. id="p-179" id="p-179" id="p-179" id="p-179" id="p-179"

[00179]In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for topical or transdermal administration. id="p-180" id="p-180" id="p-180" id="p-180" id="p-180"

[00180]In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. id="p-181" id="p-181" id="p-181" id="p-181" id="p-181"

[00181]In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.

WO 2022/002245 PCT/CN2021/104232 id="p-182" id="p-182" id="p-182" id="p-182" id="p-182"

[00182]Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), in "Remington: The Science and Practice of Pharmacy", Ed. University of the Sciences in Philadelphia, 21st Edition, LWW (2005), which are incorporated herein by reference. id="p-183" id="p-183" id="p-183" id="p-183" id="p-183"

[00183]In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form. The amount of the compounds provided herein in the single dosage form will vary depending on the subject treated and particular mode of administration. id="p-184" id="p-184" id="p-184" id="p-184" id="p-184"

[00184]In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.001-1000 mg/kg body weight/day, for example, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01- 400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-1mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body weight/day, 1-50 mg/kg body weight/day, 1-45 mg/kg body weight/day, 1-40 mg/kg body weight/day, 1-35 mg/kg body weight/day, 1-mg/kg body weight/day, 1-25 mg/kg body weight/day of the compounds provided herein, or a pharmaceutically acceptable salt thereof, can be administered. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosage regimes, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference. id="p-185" id="p-185" id="p-185" id="p-185" id="p-185"

[00185]In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and WO 2022/002245 PCT/CN2021/104232 sustained-releasing. Accordingly, the pharmaceutical formulations of the present disclosure may also be formulated for controlled release or for slow release. id="p-186" id="p-186" id="p-186" id="p-186" id="p-186"

[00186]In a further aspect, there is also provided veterinary compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route. id="p-187" id="p-187" id="p-187" id="p-187" id="p-187"

[00187]The pharmaceutical compositions or veterinary compositions may be packaged in a variety of ways depending upon the method used for administering the drug. For example, an article for distribution can include a container having deposited therein the compositions in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. id="p-188" id="p-188" id="p-188" id="p-188" id="p-188"

[00188]In a further aspect, there is also provided pharmaceutical compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient. id="p-189" id="p-189" id="p-189" id="p-189" id="p-189"

[00189]In some embodiments, the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.51 WO 2022/002245 PCT/CN2021/104232 id="p-190" id="p-190" id="p-190" id="p-190" id="p-190"

[00190]In some embodiments, the second active ingredient can include: (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like paclitaxel and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecins); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; (iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2- hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-3 54825), and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbBantibody trastuzumab [HerceptinTM] and the anti-erbBl antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine 52 WO 2022/002245 PCT/CN2021/104232 kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine(gef1tinib, ZD 1839), N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido- N-(3-chloro-4-fluorophenyl)-7-(3 -morpholinopropoxy )quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43- 9006)) and inhibitors of cell signalling through MEK and/or Akt kinases; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4- ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2- methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avp3 function and angiostatin)]; (vi) vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, such as ISIS 2503, an anti-ras antisense agent; (viii) gene therapy approaches, including approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapeutic approaches, including ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with 53 WO 2022/002245 PCT/CN2021/104232 cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine- trtnsfected tumour cell lines and approaches using anti-idiotypic antibodies.

Method of treatment of disease id="p-191" id="p-191" id="p-191" id="p-191" id="p-191"

[00191]In an aspect, the present disclosure provides compounds of Formula (I) or pharmaceutically acceptable salts thereof, which are capable of inhibiting ATR kinase. The inhibitory properties of compounds of Formula (I) may be demonstrated using the test procedures set out herein. id="p-192" id="p-192" id="p-192" id="p-192" id="p-192"

[00192]Accordingly, the compounds of Formula (I) may be used in the treatment (therapeutic or prophylactic) of conditions or diseases in a subject which are mediated by ATR kinase. id="p-193" id="p-193" id="p-193" id="p-193" id="p-193"

[00193]As used herein, a "subject" refers to a human and a non-human animal. Examples of a non-human animal include all vertebrates, e.g., mammals, such as non- human primates (particularly higher primates), dog, rodent (e.g., mouse or rat), guinea pig, cat, and non-mammals, such as birds, amphibians, reptiles, etc. In a preferred embodiment, the subject is a human. In another embodiment, the subject is an experimental animal or animal suitable as a disease model. id="p-194" id="p-194" id="p-194" id="p-194" id="p-194"

[00194]In some embodiments, the compounds of Formula (I) can be used as anti- tumour agents. In some embodiments, the compounds of Formula (I) can be used as anti-proliferative, apoptotic and/or anti-invasive agents in the containment and/or treatment of solid and/or liquid tumour disease. In certain embodiments, the compounds of Formula (I) are useful in the prevention or treatment of those tumours which are sensitive to inhibition of ATR In certain embodiments, the compounds of Formula (I) are useful in the prevention or treatment of those tumours which are mediated alone or in part by ATR. id="p-195" id="p-195" id="p-195" id="p-195" id="p-195"

[00195]In some embodiments, the compounds of Formula (I) are useful for the treatment of proliferative diseases, including malignant diseases such as cancer as WO 2022/002245 PCT/CN2021/104232 well as non-malignant diseases such as inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases. id="p-196" id="p-196" id="p-196" id="p-196" id="p-196"

[00196]In some embodiments, the compounds of Formula (I) are useful for the treatment of cancer, for example but not limited to, haematologic malignancies such as leukaemia, multiple myeloma, lymphomas such as Hodgkin's disease, non- Hodgkin's lymphomas (including mantle cell lymphoma), and myelodysplastic syndromes, and also solid tumours and their metastases such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial cancer, tumours of the central nervous system such as gliomas, dysembryoplastic neuroepithelial tumour, glioblastoma multiforme, mixed gliomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratoma, cancers of the gastrointestinal tract such as gastric cancer, oesophagal cancer, hepatocellular (liver) carcinoma, cholangiocarcinomas, colon and rectal carcinomas, cancers of the small intestine, pancreatic cancers, cancers of the skin such as melanomas (in particular metastatic melanoma), thyroid cancers, cancers of the head and neck and cancers of the salivary glands, prostate, testis, ovary, cervix, uterus, vulva, bladder, kidney (including renal cell carcinoma, clear cell and renal oncocytoma), squamous cell carcinomas, sarcomas such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal tumour (GIST), Kaposi's sarcoma, and paediatric cancers such as rhabdomyosarcomas and neuroblastomas. id="p-197" id="p-197" id="p-197" id="p-197" id="p-197"

[00197]In some embodiments, the compounds of Formula (I) are useful for the treatment of autoimmune and/or inflammatory diseases, for example but not limited to, allergy, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, coeliac disease, chagas disease, chronic obstructive pulmonary disease, chronic Idiopathic thrombocytopenic purpura (ITP), churg-strauss syndrome, Crohn's disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), graves' disease, guillain-barre syndrome, hashimoto's disease, 55 WO 2022/002245 PCT/CN2021/104232 hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjogren's disease, systemic lupus erythematosus (and associated glomerulonephritis), temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated and other vasculitides), vitiligo, and Wegener's granulomatosis. id="p-198" id="p-198" id="p-198" id="p-198" id="p-198"

[00198]As used herein, the term "therapy" is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving beneficial or desired clinical results. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Therapy" can also mean prolonging survival as compared to expected survival if not receiving it. Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. The term "therapy" also encompasses prophylaxis unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner. id="p-199" id="p-199" id="p-199" id="p-199" id="p-199"

[00199]As used herein, the term "prophylaxis" or "prophylactic" is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

WO 2022/002245 PCT/CN2021/104232 id="p-200" id="p-200" id="p-200" id="p-200" id="p-200"

[00200]The term "treatment" is used synonymously with "therapy". Similarly the term "treat" can be regarded as "applying therapy" where "therapy" is as defined herein. id="p-201" id="p-201" id="p-201" id="p-201" id="p-201"

[00201]In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure for use in therapy, for example, for use in therapy associated with ATR kinase. id="p-202" id="p-202" id="p-202" id="p-202" id="p-202"

[00202]In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer. id="p-203" id="p-203" id="p-203" id="p-203" id="p-203"

[00203]In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer. id="p-204" id="p-204" id="p-204" id="p-204" id="p-204"

[00204]In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure, for use in the treatment of cancer. id="p-205" id="p-205" id="p-205" id="p-205" id="p-205"

[00205]In some embodiments, the compounds of Formula (I) can be used further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). For instance, the compounds of Formula (I) can be used in combination with other pharmaceutically active compounds, or non- drug therapies, preferably compounds that are able to enhance the effect of the compounds of Formula (I). The compounds of Formula (I) can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other therapies. In general, a combination therapy envisions administration of two or more drugs/treatments during a single cycle or course of therapy.

WO 2022/002245 PCT/CN2021/104232 id="p-206" id="p-206" id="p-206" id="p-206" id="p-206"

[00206]In some embodiments, the compounds of Formula (I) are used in combination with one or more of traditional chemotherapeutic agents, which encompass a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purposes of shrinking tumors, destroying remaining cancer cells left over after surgery, inducing remission, maintaining remission and/or alleviating symptoms relating to the cancer or its treatment. id="p-207" id="p-207" id="p-207" id="p-207" id="p-207"

[00207]In some embodiments, the compounds of Formula (I) are used in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states. id="p-208" id="p-208" id="p-208" id="p-208" id="p-208"

[00208]In some embodiments, the compounds of Formula (I) are used in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathway, or processes. id="p-209" id="p-209" id="p-209" id="p-209" id="p-209"

[00209]In some embodiments, the compounds of Formula (I) are used in combination with one or more of other anti-cancer agents that include, but are not limited to, gene therapy, RNAi cancer therapy, chemoprotective agents (e.g. , amfostine, mesna, and dexrazoxane), drug-antibody conjugate(e.g brentuximab vedotin, ibritumomab tioxetan), cancer immunotherapy such as Interleukin-2, cancer vaccines(e.g. , sipuleucel-T) or monoclonal antibodies (e.g. , Bevacizumab, Alemtuzumab, Rituximab, Trastuzumab, etc). id="p-210" id="p-210" id="p-210" id="p-210" id="p-210"

[00210]In some embodiments, the compounds of Formula (I) are used in combination with one or more anti-inflammatory agent including but not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate. id="p-211" id="p-211" id="p-211" id="p-211" id="p-211"

[00211]In some embodiments, the compounds of Formula (I) are used in combination with radiation therapy or surgeries. Radiation is commonly delivered internally (implantation of radioactive material near cancer site) or externally from a machine that employs photon (x-ray or gamma-ray) or particle radiation. Where the combination therapy further comprises radiation treatment, the radiation treatment 58 WO 2022/002245 PCT/CN2021/104232 may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. id="p-212" id="p-212" id="p-212" id="p-212" id="p-212"

[00212]Accordingly, in a further aspect, the present disclosure provides a method for treating diseases associated with ATR kinase in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.

EXAMPLES id="p-213" id="p-213" id="p-213" id="p-213" id="p-213"

[00213]For the purpose of illustration, the following examples are included.However, it is to be understood that these examples do not limit the present disclosure and are only meant to suggest a method of practicing the present disclosure. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are deemed to be within the scope of the present disclosure. For example, the synthesis of non- exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.

Example 1 WO 2022/002245 PCT/CN2021/104232 Pd(dppf)CI2, Cs2COdioxane, 100°C H 1-2 NaOH, TBAB toluene, H2OBrettPhos-Pd-G3, Cs2COdioxane, 100°CHCl/Dioxane Step 1: methyl (R)-2-chloro-6-(3-methylmorpholino)isonicotinate (1-3) id="p-214" id="p-214" id="p-214" id="p-214" id="p-214"

[00214]To a solution of methyl 2,6-dichloropyridine-4-carboxylate (2.5 g, 12.mmol) and (3R)-3-methylmorpholine (1.35 g, 13.35 mmol) in dioxane (50 mL) were added C82CO3 (7.91 g, 24.27 mmol) and Pd(dppf)C12 (0.44 g, 0.61 mmol). The mixture was charged with N2 twice, then stirred at 100°C overnight. LC-MS showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with EA (80 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on flash column chromatography (Silica, 0-15% ethyl acetate in petroleum ether) to give the desired product (1.01g, yield: 31%). LC-MS (ESI): m/z 271 [M+H]+. 1H NMR (4MHz, DMSO)5 7.11 (d,J=0.7Hz, 1H), 7.00 (d,/=0.7 Hz, 1H), 4.32 (dd,J=6.7, 2.6 Hz, 1H), 3.96- 3.88 (m, 2H), 3.87 (s, 3H), 3.72 (d, J= 11.4 Hz, 1H), 3.61 (dd, J= 11.5, 3.0 Hz, 1H), 3.46 (td,./= 11.9, 3.1 Hz, 1H), 3.13 (td, J= 12.7, 3.9 Hz, 1H), 1.(d, 6.7 Hz, 3H).

Step 2. (R)-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)methanol (1-4) WO 2022/002245 PCT/CN2021/104232 id="p-215" id="p-215" id="p-215" id="p-215" id="p-215"

[00215]To a solution of methyl 2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridine- 4-carboxylate (4.5 g, 16.62 mmol) in THF (40 mL) at 0°C was added LiBH4 solution (2.0 M in THF, 15.0 mL, 30.0 mmol). The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with EA (60 mL><2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Silica, 0~50% ethyl acetate in petroleum ether) to give the title product (3.87 g, 96%). LC-MS(ESI): m/z 2[M+H]+. 1HNMR (400 MHz, CDCh) 5 6.58 (s, 1H), 6.46 (s, 1H), 4.62 (s, 2H), 4.-4.23 (m, 1H), 3.99 (dd, J= 11.4, 3.8 Hz, 1H), 3.86 (dd, J= 13.1, 2.9 Hz, 1H), 3.(d, J= 11.3 Hz, 1H), 3.72 (dd,./= 11.4, 2.9 Hz, 1H), 3.61-3.54 (m, 1H), 3.21 (td, J = 12.7, 3.8 Hz, 1H), 1.89 (s, 1H), 1.24 (d,J=6.7Hz, 3H).

Step 3. (R)-4-(6-chloro-4-(chloromethyl)pyridin-2-yl)-3-methylmorpholine (1-5) SOCI2DCM id="p-216" id="p-216" id="p-216" id="p-216" id="p-216"

[00216]To a solution of {2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl }methanol (4.0 g, 16.48 mmol) and DMF (0.05 mL, 0.65 mmol) in DCM (40 mL) at °C was added SOC12 (10 mL, 137.8 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction mixture was concentrated under vacuo to dryness. The residue was dissolved in DCM (50 mL), then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and 61 WO 2022/002245 PCT/CN2021/104232 concentrated to give the desired product (4.08 g, yield: 95%). LC-MS(ESI): m/z 2[M+H]+. 1HNMR (400 MHz, CDCh) 5 6.62 (s, 1H), 6.43 (s, 1H), 4.41 (s, 2H), 4.(dd, J= 6.7, 2.6 Hz, 1H), 4.00 (dd, J= 11.4, 3.8 Hz, 1H), 3.86 (dd, J= 13.1, 3.0 Hz, 1H), 3.80-3.76 (m, 1H), 3.73 (dd, J= 11.4, 2.9 Hz, 1H), 3.61-3.54 (m, 1H), 3.(td, J= 12.7, 3.9 Hz, 1H), 1.26 (d, J= 6.7 Hz, 3H).

Step 4. (R)-4-(6-chloro-4-((methylsulfonyl)methyl)pyridin-2-yl)-3-methyl morpholine (1-6) id="p-217" id="p-217" id="p-217" id="p-217" id="p-217"

[00217]A mixture of (3R)-4-[6-chloro-4-(chloromethyl)pyridin-2-yl]-3- methylmorpholine (1.50 g, 5.74 mmol) and sodium methanesulfinate (1.17 g, 11.mmol) in DMF (20 mL) was stirred at room temperature overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with H2O and extracted with EA (60 mLx2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (Silica, 0-50% ethyl acetate in petroleum ether) to give the desired product (1.55 g, yield: 89%). EC- MS(ESI): m/z 305 [M+H]+. 1HNMR (400 MHz, CDCh) 5 6.60 (s, 1H), 6.49 (s, 1H), 4.28-4.22 (m, 1H), 4.10 (s, 2H), 4.00 (dd, J= 11.5, 3.8 Hz, 1H), 3.90 (dd, J= 13.2, 2.8 Hz, 1H), 3.80 -3.76 (m, 1H), 3.72 (dd, J= 11.4, 3.0 Hz, 1H), 3.61 -3.(m, 1H), 3.23 (td, J= 12.7, 3.9 Hz, 1H), 2.85 (s, 3H), 1.26 (d,J=6.7Hz, 3H).

Step 5. (R)-4-(6-chloro-4-(l-(methylsulfonyl)cyclopropyl)pyridin-2-yl)-3-methyl morpholine (1-7) WO 2022/002245 PCT/CN2021/104232 NaOH, TBAB toluene, H2O id="p-218" id="p-218" id="p-218" id="p-218" id="p-218"

[00218]A mixture of (3R)-4-[6-chloro-4-(methanesulfonylmethyl)pyridin-2-yl]-3- methyl morpholine (1.55 g, 5.09 mmol), 1,2-dibromoethane (0.88 ml, 10.17 mmol), NaOH solution (10.0 M, 5.09 mL, 50.85 mmol) and TBAB (330 mg, 1.02 mmol) in toluene (50 mL) was stirred at 60°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with H2O and extracted with EA (60 mL*2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Silica, 0~50% ethyl acetate in petroleum ether) to give the desired product (652 mg, yield: 39%). LC-MS(ESI): m/z 3[M+H]+. 1HNMR (400 MHz, CDCh) 5 6.70 (s, 1H), 6.67 (d, J- 0.9 Hz, 1H), 4.(d, J=6.9Hz, 1H), 4.00 (dd, J= 11.4, 3.8 Hz, 1H), 3.89 (dd, J= 13.2, 2.8 Hz, 1H), 3.78 (d, J= 11.4 Hz, 1H), 3.72 (dd,./= 11.4, 3.0 Hz, 1H), 3.58 (td, J= 11.9, 3.1 Hz, 1H), 3.22 (td, J- 12.7, 3.9 Hz, 1H), 2.83 (s, 3H), 1.88 - 1.76 (m, 2H), 1.26 (d, J- 6.Hz, 5H).

Step 6. tert-butyl (R)-5-((6-(3-methylmorpholino)-4-(l- (methylsulfonyl)cyclopropyl) pyridin-2-yl)amino)-lH-pyrazole-l-carboxylate (1- 9) id="p-219" id="p-219" id="p-219" id="p-219" id="p-219"

[00219]To a solution of (3R)-4-[6-chloro-4-(l-methanesulfonylcyclopropyl)pyridin- 2-yl]-3-methylmorpholine (100 mg, 0.30 mmol) and tert-butyl 5-amino-lH-pyrazole- 1-carboxylate (83 mg, 0.45 mmol) in dioxane (10 mL) were added BrettPhos-Pd-G63 WO 2022/002245 PCT/CN2021/104232 catalyst (27 mg, 0.030 mmol) and C82CO3 (197 mg, 0.060 mmol). The mixture was charged with N2 twice, then stirred at 100°C for 4 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by flash column chromatography (Silica, 0-60% ethyl acetate in petroleum ether) to give the title product (59 mg, yield: 41%). EC- MS(ESI): m/z 478 [M+H]+ Step ר. (R)-6-(3-methylmorpholino)-4-(l-(methylsulfonyl)cyclopropyl)-N-(lH- pyrazol-5-yl)pyridin-2-amine (1) id="p-220" id="p-220" id="p-220" id="p-220" id="p-220"

[00220]A mixture of tert-butyl 5-{[4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3- methyl morpholin-4-yl]pyridin-2-yl]amino}-lH-pyrazole-l-carboxylate (59 mg, 0.mol) and HC1 solution (4 M in dioxane, 2 mL) in DCM (2 mL) was stirred at room temperature for 2 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under vacuo to dryness. The residue was purified by Prep- HPLC (Cl8, 20-95%, acetonitrile in H2O with 0.1% HCOOH) to give the desired product (14.2 mg, yield 30%). LC-MS (ESI): m/z 378 [M+H]+. 1H NMR (4MHz, DMSO) 5 9.14 (s, 1H), 7.57 (d, J = 2.2 Hz, 1H), 6.60 (s, 1H), 6.28 (d, J= 2.Hz, 1H), 6.23 (s, 1H), 4.26 (d, J= 6.6 Hz, 1H), 3.94 (dd, J = 11.3, 3.3 Hz, 1H), 3.(d, 13.0 Hz, 1H), 3.73 (d, J= 11.2 Hz, 1H), 3.65-3.61 (m, 1H), 3.51 (s, 1H), 3.08(d, J = 3.6 Hz, 1H), 2.95 (s, 3H), 1.57 (dd, J= 5.8, 4.0 Hz, 2H), 1.26 (dd, J= 6.3, 4.Hz, 2H), 1.14 (d, J= 6.6 Hz, 3H).

Example 2 WO 2022/002245 PCT/CN2021/104232 2-3 2-4 TolueneTBAB, NaOH/H2OdioxaneBrettphos Pd G3, Cs2CO3 Step 1. (2,6-dichloro-3-methylpyridin-4-yl)methanol (2-2) id="p-221" id="p-221" id="p-221" id="p-221" id="p-221"

[00221]To a solution of ethyl 2,6-dichloro-3-methylpyridine-4-carboxylate (290 mg, 1.24 mmol) in anhydrous THF (5 mL) at 0 °C was added LiBH4 solution (2.0 M in THF, 0.68 mL, 1.37 mmol) drop wise under N2 atmosphere. The resulting mixture was stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NH4C1 aqueous solution and extracted with EA (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by column chromatography on silica gel (PE : EA =5:1, V/V) to give the desired product (220 mg, yield: 92%). LC/MS (ESI): m/z 192 [M+H]+.

Step 2.2,6-dichloro-4-(chloromethyl)-3-methylpyridine (2-3) id="p-222" id="p-222" id="p-222" id="p-222" id="p-222"

[00222]To a solution of (2,6-dichloro-3-methylpyridin-4-yl)methanol (220 mg, 1.mmol) and DMF (0.01 mL) in anhydrous DCM (5 mL) at 0 °C was added SOC12 (4mg, 3.44 mmol) drop wise. The resulting mixture was stirred at room temperature for h. LC-MS showed the reaction was complete. The reaction mixture was WO 2022/002245 PCT/CN2021/104232 concentrated under reduced pressure. The residue was diluted with EA (40 mL), then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was used in the next step without further purification (230 mg, yield: 95%). LC/MS (ESI): m/z 210/2[M+H]+ Step 3. 2,6-dichloro-3-methyl-4-((methylsulfonyl)methyl)pyridine morpholine (2- 4) id="p-223" id="p-223" id="p-223" id="p-223" id="p-223"

[00223]A mixture of 2,6-dichloro-4-(chloromethyl)-3-methylpyridine (259 mg, 1.mmol) and CH3SO2Na (253 mg, 2.48 mmol) in DMF (5 mL) was stirred at room temperature for 4 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to afford the desired product (2mg, yield: 86%). LC/MS (ESI): m/z 254 [M+H]+.

Step 4. (R)-4-(6-chIoro-5-methyI-4-((methyIsulfonyl)methyl)pyridin-2-yI)-3- methyl morpholine (2-6) id="p-224" id="p-224" id="p-224" id="p-224" id="p-224"

[00224]A mixture of 2,6-dichioro-4-(methanesulfonylmethyl)-3-methylpyridine (2mg, 0.98 mmol), (3 R)-3-methylmorpholine (399 mg, 3.94 mmol) and DIPEA (5mg, 3.94 mmol) in NMP (3 mL) was stirred at 180 °C for 1 h under microwave irradiation. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous66 WO 2022/002245 PCT/CN2021/104232 Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to afford the desired product as a white solid (97 mg, yield: 30%). LC/MS (ESI): m/z 319 [M+H]+.

Step 5. (R)-4-(6-chloro-5-methyl-4-(l-(methylsulfonyl)cyclopropyl)pyridin-2-yl)- 3-methylmorpholine (2-7) id="p-225" id="p-225" id="p-225" id="p-225" id="p-225"

[00225]A mixture of (3R)-4-[6-chloro-4-(methanesulfonylmethyl)-5-methylpyridin- 2-yl]-3-methylmorpholine (97 mg, 0.30 mmol), 1,2-dibromoethane (113 mg, 0.mmol), NaOH (10.0 M in H:O, 0.3 mL, 3.05 mmol) and TBAB (19 mg, 0.06 mmol) in Toluene (4 mL) was stirred at 60 °C for 3 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to afford the desired product (29 mg, yield: 27%). LC/MS (ESI): m/z 345 [M+H]+.

Step 6. (R)-3-methyl-6-(3-methylmorpholino)-4-(l-(methylsulfonyl)cyclopropyl)- N-(lH-pyrazol-5-yl)pyridin-2-amine (2) id="p-226" id="p-226" id="p-226" id="p-226" id="p-226"

[00226]To a solution of (3R)-4-[6-chloro-4-(l-methanesulfonylcyclopropyl)-5- methylpyridin-2-yl]-3-methylmorpholine (30 mg, 0.08 mmol) and lH-pyrazol-5- amine (14 mg, 0.16 mmol) in dioxane (1.5 mL) were added BrettPhos Pd G3 (8 mg, 0.01 mmol) and C82CO3 (85 mg, 0.26 mmol). The mixture was stirred at 110 °C for 1067 WO 2022/002245 PCT/CN2021/104232 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (17 mg, yield: 49%). LC/MS (ESI): m/z 392 [M+H]+. 1HNMR (400 MHz, DMSO) 5 12.09 (s, 1H),7.94 (s, 1H), 7.52 (s, 1H), 6.40 (s, 1H), 6.24 (s, 1H), 4.20 (d, J = 5.0 Hz, 1H), 3.92 (dd, J= 11.2, 3.1 Hz, 1H), 3.71 (d, J = 11.4 Hz, 2H), 3.62 (dd, J= 11.2, 2.7 Hz, 1H), 3.47 (td, J - 11.8, 2.9 Hz, 1H), 3.06 - 2.98 (m, 1H), 2.95 (s, 3H), 2.17 (s, 3H), 1.87 (s, 1H), 1.52 (s, 1H), 1.24 (s, 2H), 1.09 (d, J = 6.1 Hz, 3H).

Example 3 Step 1. (R)-3-methyl-N-(3-methyl-lH-pyrazol-5-yl)-6-(3-methylmorpholino)-4-(l- (methylsulfonyl)cyclopropyl)pyridin-2-amine (3) id="p-227" id="p-227" id="p-227" id="p-227" id="p-227"

[00227]To a solution of (3R)-4-[6-chloro-4-(l-methanesulfonylcyclopropyl)-5- methylpyridin-2-yl]-3-methylmorpholine (50 mg, 0.14 mmol) and 3-methyl-lH- pyrazol-5-amine (28 mg, 0.28 mmol) in dioxane (2 mL) were added BrettPhos-Pd-G(13 mg, 0.01 mmol) and C82CO3 (142 mg, 0.43 mmol). The mixture was stirred at 1°C for 10 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (54 mg, yield: 91%). LC/MS (ESI): m/z 406 [M+H]+. 1HNMR (400 MHz,68 WO 2022/002245 PCT/CN2021/104232 DMSO) 8 11.75 (s, 1H), 7.69 (s, 1H), 6.21 (s, 2H), 4.20 (s, 1H), 3.92 (d, J = 8.2 Hz, 1H), 3.71 (d, J = 11.3 Hz, 2H), 3.62 (d, J = 8.8 Hz, 1H), 3.47 (dd, J= 11.4, 8.9 Hz, 1H), 3.01 (t, J = 10.9 Hz, 1H), 2.94 (s, 3H), 2.17 (d, J = 15.2 Hz, 6H), 1.86 (s, 1H), 1.51 (s, 1H), 1.23 (s, 2H), 1.10 (d, 1 = 5.9 Hz, 3H).

Example 4 Pd(dppf)CI2Na2CO3, DMECs2CO3,dioxaneBrettPhos Pd G3 4-6 B0C Step 1. 2,6-dichloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)pyridine (4-3) Cl Pd(dppf)CI2Na2CO3, DME id="p-228" id="p-228" id="p-228" id="p-228" id="p-228"

[00228]To a solution of 2,6-dichloro-4-iodopyridine (300 mg, 1.10 mmol) and 1,4- dimethyl-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (267.6 mg, 1.mmol) in DME (10 mL) were added Na2CO3 (232.2 mg, 2.19 mmol) and Pd(dppf)C(80.2 mg, 0.11 mmol). The mixture was charged with N2 twice, then stirred at 90°C for 4 h. EC-MS showed the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with EA (40 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Prep-TLC (PE:EA =3:1, WO 2022/002245 PCT/CN2021/104232 V/V) to afford the desired product (230 mg, yield: 86 %). LC/MS (ESI) m/z: 2[M+H]+.

Step 2. (R)-4-(6-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)pyridin-2-yl)-3-methyl morpholine (4-5) id="p-229" id="p-229" id="p-229" id="p-229" id="p-229"

[00229]To a solution of 2,6-dichloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)pyridine (2mg, 0.95 mmol) in NMP (3 mL) was added (3R)-3-methylmorpholine (384.4 mg, 3.mmol). The reaction was stirred at 150 °C for 1 h under microwave irradiation.LC-MS showed the reaction was complete. The mixture was diluted with water (mL) and extracted with EA (40 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo.The residue was purified by flash column chromatography (Silica, 0-10% ethyl acetate in petroleum ether) to afford the desired product (150 mg, yield: 51%). LC/MS (ESI) m/z: 307 [M+H]+.

Step 3. tert-butyl (R)-5-((4-(l,4-dimethyMH-pyrazol-5-yl)-6-(3- methylmorpholino) pyridin-2-yl)amino)-lH-pyrazole-l-carboxylate (4-7) Cs2CO3,dioxaneBrettPhos Rd G3 id="p-230" id="p-230" id="p-230" id="p-230" id="p-230"

[00230]To a solution of (R)-4-(6-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)pyridin-2- yl) -3-methylmorpholine (120 mg, 0.39 mmol) and tert-butyl 5-amino-lH-pyrazole- 1-carboxylate (107.49 mg, 0.587 mmol) in dioxane (10 mL) were added CS2CO(637.2 mg, 1.96 mmol) and BrettPhos Pd G3 (35.46 mg, 0.04 mmol). The mixture WO 2022/002245 PCT/CN2021/104232 was charged with N2 twice, then stirred at 90°C overnight. LC-MS showed the reaction was complete. The reaction was diluted with water (30 mL) and extracted with EA (40 mLx2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Prep-TLC (PE:EA = 2:1, V/V) to afford the desired product (80 mg, yield: 45 %). LC/MS (ESI) m/z: 454 [M+H]+.

Step 4. (R)-4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-(3-methylmorpholino)-N-(lH- pyrazol-5-yl)pyridin-2-amine (4) HCI/dioxane id="p-231" id="p-231" id="p-231" id="p-231" id="p-231"

[00231]A mixture of tert-butyl (R)-5-((4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-(3-methyl morpholino)pyridin-2-yl)amino)-lH-pyrazole-l-carboxylate (80 mg, 0.18 mmol) in HC1 solution (4M in dioxane, 2 mL) was stirred at room temperature overnight. EC- MS showed the reaction was complete. The reaction mixture was concentrated under vacuo to dryness. The residue was purified by Pre-HPLC (C18, 20-95%, acetonitrile in H2O with 0.1% TEA) to afford the desired product (20 mg, yield: 32%). LC/MS (ESI) m/z: 354 [M+H]+. 1H NMR (400 MHz, DMSO) 5 9.05 (s, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.31 (s, 1H), 6.41 (s, 1H), 6.35 (d, J = 1.9 Hz, 1H), 6.(s, 1H), 4.30 (d, J = 6.8 Hz, 1H), 3.97 - 3.84 (m, 2H), 3.74 (s, 3H), 3.71 (s, 1H), 3.63(dd, J = 11.3, 2.8 Hz, 1H), 3.52 - 3.45 (m, 1H), 3.11 - 3.03 (m, 1H), 1.99 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H).

Example 5 WO 2022/002245 PCT/CN2021/104232 Et3N, DCM 50 % NaOH, TBAB Toluene, 60 °CPd2(dba)3, Xant-Phos, Cs2CO3, dioxane, 100 °C Step 1. methyl(R)-2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (5- 3) id="p-232" id="p-232" id="p-232" id="p-232" id="p-232"

[00232]A mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (1.5 g, 7.mmol), (3 R)-3-methylmorpholine (732 mg, 7.24 mmol) and TEA (1.47 g, 14.mmol) in DCM (30 mL) was stirred at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM (20 mL), then washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA= 3:1, V/V) to afford the desired product (1.55 g, yield: 78%).LC/MS( ESI): m/z 272 [M+H]+.

Step 2. (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (5-4) WO 2022/002245 PCT/CN2021/104232 id="p-233" id="p-233" id="p-233" id="p-233" id="p-233"

[00233]To a solution of methyl 2-chloro-6-[(3R)-3-methylmorpholin-4- yl]pyrimidine-4-carboxylate (1 g, 3.67 mmol) in anhydrous THF (20 mL) at 0 °C was added LiBH4 solution (2.0 M in THF, 3.7 mL, 7.34 mmol) dropwise under Natmosphere. The resulting mixture was stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to give the desired product (800 mg, yield: 89%). LC/MS (ESI): m/z 244 [M+H]+.

Step 3. (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (5-5) id="p-234" id="p-234" id="p-234" id="p-234" id="p-234"

[00234]To a solution of {2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4- yl}methanol (800 mg, 3.28 mmol) and DMF (0.01 mL) in anhydrous DCM (20 mL) at 0 °C was added SOC12 (1.17 g, 9.84 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EA (40 mL), then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was used in the next step without further purification (800 mg, yield: 93%). LC/MS (ESI): m/z 262/264 [M+H]+ Step 4. (R)-4-(2-chloro-6-((methylsulfonyl)methyl)pyrimidin-4-yl)-3-methyl morpholine (5-6) WO 2022/002245 PCT/CN2021/104232 CH3SO2NaDMF id="p-235" id="p-235" id="p-235" id="p-235" id="p-235"

[00235]A mixture of (3R)-4-[2-chloro-6-(chloromethyl)pyrimidin-4-yl]-3- methylmorpholine (535 mg, 2.04 mmol) and CH3SO2Na (418 mg, 4.10 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 2:1, V/V) to afford the desired product (560 mg, yield: 90%). LC/MS( ESI): m/z 306 [M+H]+.

Step 5. (R)-4-(2-chloro-6-(l-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)-3- methyl morpholine (5-7) id="p-236" id="p-236" id="p-236" id="p-236" id="p-236"

[00236]A mixture of (3R)-4-[2-chloro-6-(methanesulfonylmethyl)pyrimidin-4-yl]-3- methylmorpholine (125 mg, 0.41 mmol), 1,2-dibromoethane (154 mg, 0.82 mmol), NaOH (10.0 M in H:O, 0.4 mL, 4.0 mmol) and TBAB (26 mg, 0.08 mmol) in Toluene (4 mL) was stirred at 60 °C for 3 h. LC-MS showed the reaction was complete.The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to afford the desired product (110 mg, yield: 81%). LC/MS( ESI): m/z 332 [M+H]+.

Step 6. tert-butyl (R)-5-((4-(3-methylmorpholino)-6-(l- (methylsulfonyl)cyclopropyl) pyrimidin-2-yl)amino)-lH-pyrazole-l-carboxylate ( 9 ־ 5 ) 74 WO 2022/002245 PCT/CN2021/104232 Pd2(dba)3, Xant-Phos, Cs2CO3, dioxane, 100 °C id="p-237" id="p-237" id="p-237" id="p-237" id="p-237"

[00237]To a solution of (3R)-4-[2-chloro-6-(l-methanesulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine (200 mg, 0.mmol) and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (166 mg, 0.90 mmol) in Dioxane (10 mL) were added Pd2(dba)3 (55 mg, 0.06 mmol), Xant-Phos (34 mg, 0.mmol) and C82CO3 (394 mg, 1.21 mmol). The mixture was stirred at 100 °C for 6 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 1:2, V/V) to afford the desired product (1mg, yield: 44%). LC/MS( ESI): m/z 479 [M+H]+.

Step ר. (R)-4-(3-methylmorpholino)-6-(l-(methylsulfonyl)cyclopropyl)-N-(lH- pyrazol-5-yl)pyrimidin-2-amine (5) HCI/dioxane id="p-238" id="p-238" id="p-238" id="p-238" id="p-238"

[00238]A mixture of tert-butyl5-{[4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3- methyl morpholin-4-yl]pyrimidin-2-yl]amino}-lH-pyrazole-l-carboxylate (60 mg, 0.12 mmol) in HC1 solution (4.0 M in dioxane, 3.0 mL) was stirred at room temperature for 10 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (20 mg, yield: 42 %). LC/MS (ESI): m/z 379 [M+H]+. 1H NMR (400 MHz, DMSO) 5 12.29 (s, 1H), 9.51 (s, 1H),7.58 (s, 1H), 6.38 (s, 2H), 4.44 (s, 1H), 4.05 (d, J75 WO 2022/002245 PCT/CN2021/104232 = 12.8 Hz, 1H), 3.94 (dd, J = 11.4, 3.4 Hz, 1H), 3.74 (d, J = 11.4 Hz, 1H), 3.59 (dd, J = 11.5, 2.9 Hz, 1H), 3.46 (s, 1H), 3.25 (s, 3H), 3.18 (s, 1H), 1.60 (t, J = 5.7 Hz, 2H), 1.50 (s, 2H), 1.21 (d, J = 6.7 Hz, 3H).

Example 6 -7 Pd2(dba)3, Xant-phosDioxane, 100 °CHCVDioxane Step 1. tert-butyl 5-{[4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3- methylmorpholin -4-yl]pyrimidin-2-yl]amino}-3-methyl-lH-pyrazole-l- carboxylate (6-2) Pd2(dba)3,Xant-phosDioxane, 100 °C id="p-239" id="p-239" id="p-239" id="p-239" id="p-239"

[00239]To a solution of (3R)-4-[2-chloro-6-(l- methanesulfonylcyclopropyl)pyrimidin-4-yl] -3-methylmorpholine (100 mg, 0.mmol) and tert-butyl 5-amino-3-methyl-lH -pyrazole-1-carboxylate (89.2 mg, 0.mmol) in Dioxane (5 mL) was added C82CO3 (196.4 mg, 0.60 mmol), Xant-Phos (17.4 mg, 0.03 mmol) and Pd2(dba)3 (24.4 mg, 0.03 mmol). The mixture was stirred at 100 °C for 6 h under nitrogen atmosphere. id="p-240" id="p-240" id="p-240" id="p-240" id="p-240"

[00240] LC-MSshowed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to afford the desired product (1mg, yield: 87%). LC/MS (ESI): m/z 493 [M+H]+.

WO 2022/002245 PCT/CN2021/104232 Step 2. 4-(l-methanesulfonylcyclopropyl)-N-(3-methyl-lH-pyrazol-5-yl)-6-[(3R)- 3-methylmorpholin-4-yl]pyrimidin-2-amine (6) id="p-241" id="p-241" id="p-241" id="p-241" id="p-241"

[00241]To a solution of tert-butyl 5-{[4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3- methyl morpholin-4-yl]pyrimidin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate (120 mg, 0.24 mmol) in DCM (2 mL) was added HC1 solution (4 M in dioxane, mL). The mixture was stirred at room temperature for 2 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under vacuo. The residue was purified by Prep-HPLC (Cl 8, 10-95% MeCN in H2O with 0.1% ammonia) to give the desired product (32.6 mg, yield: 34%). LC/MS (ESI) m/z: 3[M+H]+. 1HNMR (400 MHz, DMSO) 5 9.21 (s, 1H), 6.31 (s, 1H), 6.15 (s, 1H), 4.40 (s, 1H), 4.02 (d, J = 11.7 Hz, 1H), 3.93 (d, 1 = 8.1 Hz, 1H), 3.73 (d, J= 11.3 Hz, 1H), 3.58 (dd, J = 11.6, 2.9 Hz, 2H), 3.25 (s, 3H), 3.16 (d, J = 10.8 Hz, 1H), 2.19 (s, 3H), 1.58 (s, 2H), 1.47 (s, 2H), 1.20 (d, J = 6.7 Hz, 3H). id="p-242" id="p-242" id="p-242" id="p-242" id="p-242"

[00242]Compound 6 can be prepared using the following scheme: (Boc )2ONaH, THF 6-3 -7 6-3' Brettphos- Pd-G3, Cs2CO3] dioxane Step 1. tert-butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (6-3) WO 2022/002245 PCT/CN2021/104232 (Boc) 2ONaH, THF id="p-243" id="p-243" id="p-243" id="p-243" id="p-243"

[00243]To a solution of 3-methyl-lH-pyrazol-5-amine (25 g, 257.41 mmol) in THF (800 mL) at 0 °C was added NaH (60%, 10.81 g, 270.28 mmol) portion wise. After stirring at 0 °C for 30 min, (Boc)2O (58.99 g, 270.28 mmol) was added in one portion. The mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction mixture was poured into saturated NH4Cl aqueous solution and extracted with DCM (600 mLx2) twice. The combined organic layer was separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =2:1, V/V) to give the desired product (19 g, yield: 37.42%). HNMR (400 MHz, CDCI3) 5 5.59 (d,J = 0.9 Hz, 1H), 3.89 (s, 2H), 2.44 (d,J = 0.9 Hz, 3H), 1.62 (s, 9H).

Step 2. (R)-tert-butyl 5-methyl-3-((4-(3-methylmorpholino)-6-(l-(methyl sulfonyl)cyclopropyl)pyrimidin-2-yl)amino)-lH-pyrazole-l-carboxylate (6-4) id="p-244" id="p-244" id="p-244" id="p-244" id="p-244"

[00244]To a solution of (3R)-4-[2-chloro-6-(l- methanesulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine (15.0 g, 45.mmol) and tert-butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (10.7 g, 54.mmol) in Dioxane (600 mL) were added BrettPhos-Pd-G3 (906 mg, 4.41 mmol) and C82CO3 (29.45 g, 90.4 mmol). The mixture was stirred at 100 °C overnight under Natmosphere. The reaction mixture was diluted with EA(1.0 L), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM : MeOH = 20 : 1, V/V) to afford the desired product (17 g, yield: 76%). LC/MS (ESI): m/z 493 [M+H]+.

Step 3. (R)-N-(3-methyl-lH-pyrazol-5-yl)-4-(3-methylmorpholino)-6-(l- 78 WO 2022/002245 PCT/CN2021/104232 (methylsulfonyl)cyclopropyl)pyrimidin-2-amine (6) id="p-245" id="p-245" id="p-245" id="p-245" id="p-245"

[00245]A mixture of (R)-tert-butyl 5-methyl-3-((4-(3-methylmorpholino)-6-(l- (methyl sulfonyl)cyclopropyl)pyrimidin-2-yl)amino)-lH-pyrazole-l-carboxylate (17.g, 34.51 mmol) in HC1 solution (4.0 M in dioxane, 100.0 mL) was stirred at room temperature for 12h. The reaction mixture was concentrated under reduced pressure to dryness, the residue was diluted with EA (200 mL) and saturated NaHCO3 aqueous solution (200 mL). The resulting mixture was stirred at room temperature overnight. The organic layer was separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (C18, 10- 95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (10 g, yield: %). LC/MS (ESI): m/z 393 [M+H]+. 1HNMR (400 MHz, DMSO) 5 11.78 (s, 1H), 9.10 (s, 1H), 6.23 (d, J = 29.9 Hz, 2H), 4.38 (s, 1H), 4.07 -3.87 (m, 2H), 3.73 (d, J = 11.4 Hz, 1H), 3.58 (dd, J= 11.5, 2.9 Hz, 1H), 3.43 (td, J = 11.8, 2.9 Hz, 1H), 3.26 (s, 3H), 3.13 (td, J = 12.9, 3.7 Hz, 1H), 2.19 (s, 3H), 1.19 (d, J = 6.7 Hz, 3H).

Example 7 -6 t-BuONa, CH3I DMFH2NBrettphos Rd G3052003, dioxane, 110 °C Step 1. (R)-4-(2-chloro-6-(2-(methylsulfonyl)propan-2-yl)pyrimidin-4-yl)-3- methyl morpholine (7-1) WO 2022/002245 PCT/CN2021/104232 t-BuONa, CH3I DMF id="p-246" id="p-246" id="p-246" id="p-246" id="p-246"

[00246]To a solution of (3R)-4-[2-chloro-6-(methanesulfonylmethyl)pyrimidin-4-yl]- 3-methylmorpholine (900 mg, 2.94 mmol) and t-BuONa (849 mg, 8.82 mmol) in anhydrous DMF (16 mL) at 0 °C was added a solution of CH3I (1.26 g, 8.85 mmol) in anhydrous DMF (1 mL) dropwise. After the addition, the resulting mixture was stirred at room temperature for 3 h. LC-MS showed the reaction was complete.The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 10:1, V/V) to afford the desired product (870 mg, yield: 88%). LC/MS( ESI): m/z 334 [M+H]+.

Step 2. (R)-4-(3-methylmorpholino)-6-(2-(methylsulfonyl)propan-2-yl)-N-(lH- pyrazol-5-yl)pyrimidin-2-amine (7) Brettphos Rd G3Cs2CO3, dioxane, 110 °C id="p-247" id="p-247" id="p-247" id="p-247" id="p-247"

[00247] Amixture of (3R)-4-[2-chloro-6-(2-methanesulfonylpropan-2-yl)pyrimidin- 4-yl]-3-methylmorpholine (100 mg, 0.30 mmol), lH-pyrazol-5-amine (37 mg, 0.mmol), BrettPhos Pd G3 (27 mg, 0.03 mmol) and C82CO3 (293 mg, 0.90 mmol) in Dioxane (5 mL) was stirred at 110 °C for 10 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (36.7 mg, yield: 32%). LC/MS (ESI): m/z 381 [M+H]+. 1H NMR (400 MHz, DMSO) 5 12.18 (s, 1H), 9.(s, 1H), 7.52 (s, 1H), 6.41 (s, 1H), 6.30 (s, 1H), 4.42 (s, 1H), 4.03 (d, J = 12.9 Hz, WO 2022/002245 PCT/CN2021/104232 1H), 3.94 (dd, J = 11.4, 3.3 Hz, 1H), 3.73 (d, J = 11.4 Hz, 1H), 3.59 (dd, J = 11.5, 3.Hz, 1H), 3.44 (dd, J= 11.8, 9.0 Hz, 1H), 3.14 (td, J= 12.9, 3.7 Hz, 1H), 3.01 (s, 3H), 1.67 (s, 6H), 1.19 (d, J = 6.7 Hz, 3H).

Example 8 Brettphos Pd G3Cs2CO3, dioxane, 110 °C Step 1. (R)-N-(3-methyl-lH-pyrazol-5-yl)-4-(3-methylmorpholino)-6-(2- (methylsulfonyl)propan-2-yl)pyrimidin-2-amine (8) Brettphos Pd G3Cs2CO3, dioxane, 110 °C id="p-248" id="p-248" id="p-248" id="p-248" id="p-248"

[00248]A mixture of (3R)-4-[6-chloro-4-(2-methanesulfonylpropan-2-yl)pyri din-2- yl]-3-methylmorpholine (100 mg, 0.30 mmol), 3-methyl-lH-pyrazol-5-amine (58 mg, 0.60 mmol), BrettPhos Pd G3 (27 mg, 0.03 mmol) and C82CO3 (293 mg, 0.90 mmol) in dioxane (4 mL) was stirred at 110 °C for 10 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product as a white solid (44.mg, yield: 37%). LC/MS (ESI): m/z 395 [M+H]+. 1H NMR (400 MHz, DMSO) 11.98 (s, 1H), 9.08 (s, 1H), 8.13 (s, 1H), 6.28 (s, 1H), 6.16 (s, 1H), 4.40 (s, 1H), 4.(d, J= 13.0 Hz, 1H), 3.93 (dd, J= 11.4, 3.4 Hz, 1H), 3.73 (d, J = 11.4 Hz, 1H), 3.(dd, J = 11.5, 2.9 Hz, 1H), 3.44 (td, J = 11.8, 2.8 Hz, 1H), 3.13 (td, J = 13.0, 3.7 Hz, 1H), 3.01 (s, 3H), 2.18 (s, 3H), 1.66 (s, 6H), 1.19 (d, J = 6.7 Hz, 3H).

Example 9 81 WO 2022/002245 PCT/CN2021/104232 MsCl.TEADCMNaCNDMSO 9-2 Brettphos Rd G3 9-3 Step 1. (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methylmethane sulfonate (9-1) id="p-249" id="p-249" id="p-249" id="p-249" id="p-249"

[00249]To a solution of (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4- yl)methanol (1 g, 4.10 mmol) and TEA (623 mg, 6.15 mmol) in DCM (30 mL) at 0 °C was added a solution of MsCl (564 mg, 4.92 mmol) in DCM (2 mL) dropwise. The resulting mixture was stirred at room temperature for 3h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA= 10:1, V/V) to afford the desired product (1.06 mg, yield: 80%). LC/MS( ESI): m/z 322 [M+H]+.

Step 2. (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)acetonitrile (9-2) NaCNDMSO WO 2022/002245 PCT/CN2021/104232 id="p-250" id="p-250" id="p-250" id="p-250" id="p-250"

[00250]To a solution of NaCN (184 mg, 3.75 mmol) in DMSO (20 mL) was added a solution of (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (1 g, 3.10 mmol) dropwise. The resulting mixture was stirred at room temperature for Ih. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with ice-water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA= 3:1, V/V) to afford the desired product (300 mg, yield: 38%). LC/MS( ESI): m/z 253 [M+H]+.

Step 3. (R)-l-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclopropane carbonitrile (9-3) id="p-251" id="p-251" id="p-251" id="p-251" id="p-251"

[00251]To a solution of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4- yl)acetonitrile (100 mg, 0.40 mmol), 1,2-dibromoethane (338 mg, 1.79 mmol) and TBAB (32.2 mg, 0.1 mmol) in 2-MeTHF (15 mL) was added a solution of KOH (1.g, 28.0 mmol) in H2O (15 mL). The resulting mixture was stirred at room temperature for 12h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =5:1, V/V) to afford the desired product (mg, yield: 46%). LC/MS( ESI): m/z 279 [M+H]+.

Step 4. (R)-l-(2-((3-methyl-lH-pyrazol-5-yl)amino)-6-(3- methylmorpholino)pyrimidin-4-yl)cyclopropanecarbonitrile (9) WO 2022/002245 PCT/CN2021/104232 Brettphos Pd G3 id="p-252" id="p-252" id="p-252" id="p-252" id="p-252"

[00252]To a solution of (R)-l-(2-chloro-6-(3-methylmorpholino)pyrimidin-4- yl)cyclo propanecarbonitrile (50 mg, 0.18 mmol), 3-methyl-lH-pyrazol-5-amine (mg, 0.36 mmol) and C82CO3 (117.3 mg, 0.36 mmol) in Dioxane (5 mL) was added BrettPhos Pd G3 (16 mg, 0.018 mmol). The mixture was stirred at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Prep-HPLC (C18, 10- 95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (8.2 mg, yield: 13%). LC/MS (ESI): m/z 340 [M+H]+. 1H NMR (400 MHz, DMSO) 5 8.97 (s, 1H), 6.17 (s, 2H), 4.35 (s, 1H), 4.04-3.87 (m, 2H), 3.72 (d, J= 11.4 Hz, 1H), 3.(dd, J= 11.5, 2.9 Hz, 1H), 3.47-3.39 (m, 4H), 3.13 (td, J= 12.9, 3.7 Hz, 2H), 2.(s, 3H), 1.70 (s, 4H), 1.19 (d, J= 6.7 Hz, 3H).

Example 10 9-2 CH3l,t-BuONaTHF 1) Brettphos Pd G3, Cs2COdioxane, 100°C2) HCI/Dioxane 10-1 Boc 10-2 Step 1. (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)-2-methyl propanenitrile (10-1) WO 2022/002245 PCT/CN2021/104232 id="p-253" id="p-253" id="p-253" id="p-253" id="p-253"

[00253]To a solution of (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl )methyl methanesulfonate (360 mg, 1.42 mmol) and t-BuONa (274 mg, 2.85 mmol) in anhydrous THF (15 mL) at 0 °C was added a solution of CH3I (605 mg, 4.26 mmol) in anhydrous THF (1 mL) dropwise. After the addition, the resulting mixture was stirred at room temperature for 12 h. LC-MS showed the reaction was complete.The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 5:1, V/V) to afford the desired product (300 mg, yield: 75%). LC/MS( ESI): m/z 281 [M+H]+.

Step 2. (R)-2-methyl-2-(2-((3-methyl-lH-pyrazol-5-yl)amino)-6-(3- methylmorpho-lino)pyrimidin-4-yl)propanenitrile (10) 1) Brettphos Pd G3, Cs2COdioxane, 100°C2) HCI/Dioxane id="p-254" id="p-254" id="p-254" id="p-254" id="p-254"

[00254]To a solution of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)-2- methyl propanenitrile (50 mg, 0.18 mmol), tert-butyl 5-amino-3-methyl-lH-pyrazole- 1-carboxylate (70 mg, 0.36 mmol) and C82CO3 (174 mg, 0.53 mmol) in Dioxane (mL) was added BrettPhos Pd G3 (16 mg, 0.018 mmol). The mixture was stirred at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was dissolved in DCM (4 mL), then HC1 solution (4M in dioxane, 2 mL) was added.The mixture was stirred at room temperature for 2h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under vacuo. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (8 mg, yield: 13%). LC/MS (ESI): m/z 342 [M+H]+. 1HNMR (400 MHz, DMSO) 6 11.78 (s, 1H), 9.07 (s, 1H), 6.26 (d, J = 17.8 Hz, 2H), 4.40 (dd, J = 13.5, 7.2 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H), 3.93 (dd, J= 11.3, 3.3 Hz, 1H), 3.72 (d, WO 2022/002245 PCT/CN2021/104232 J = 11.4 Hz, 1H), 3.58 (dd, J = 11.4, 2.9 Hz, 1H), 3.45 -3.42 (m, 1H), 3.17-3.10 (m, 1H), 2.17 (s, 3H), 1.64 (s, 6H), 1.19 (d, J = 6.7 Hz, 3H).

Example 11 NaOH/H2Ol TBAB, DCM Brettphos Rd G3, Cs2CO3dioxane, 110 °C Step 1. (R)-4-(2-chloro-6-(4-(methylsulfonyl)tetrahydro-2H-pyran-4- yl)pyrimidin-4-yl)-3-methylmorpholine (11-1) id="p-255" id="p-255" id="p-255" id="p-255" id="p-255"

[00255]A mixture of (3R)-4-[2-chloro-6-(methanesulfonylmethyl)pyrimidin-4-yl]-3- methyl morpholine (400 mg, 1.31 mmol), l-bromo-2-(2-bromoethoxy)ethane (9mg, 3.93 mmol), TBAB (42 mg, 0.13 mmol) and NaOH (10.0 M in H:O, 1.31 mb, 13.1 mmol) in DCM (20 mL) was stirred at room temperature for 24 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by column chromatography on silica gel (PE : EA =3:1, V/V) to afford the desired product (147 mg, yield: 30%). LC/MS (ESI): m/z 376 [M+H]+ Step 2. (R)-4-(3-methylmorpholino)-6-(4-(methylsulfonyl)tetrahydro-2H-pyran- 4-yl)-N-(lH-pyrazol-5-yl)pyrimidin-2-amine (11) WO 2022/002245 PCT/CN2021/104232 Brettphos Rd G3, Cs2COdioxane, 110 °C id="p-256" id="p-256" id="p-256" id="p-256" id="p-256"

[00256]A mixture of (3R)-4-[2-chloro-6-(4-methanesulfonyloxan-4-yl)pyrimidin-4- yl]-3-methylmorpholine (70 mg, 0.19 mmol), lH-pyrazol-5-amine (31 mg, 0.mmol), BrettPhos Pd G3 (17 mg, 0.02 mmol) and C82CO3 (182 mg, 0.56 mmol) in Dioxane (3 mL) was stirred at 110 °C for 10 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (40 mg, yield: 50%). LC/MS (ESI): m/z 423 [M+H]+. 1H NMR (400 MHz, DMSO) 6 12.09 (s, 1H), 9.(s, 1H), 7.53 (s, 1H), 6.40 (s, 2H), 4.41 (d, J = 4.6 Hz, 1H), 4.08 (d, J = 12.8 Hz, 1H), 3.91 (ddd, J= 16.0, 10.8,4.0 Hz, 3H), 3.73 (d, J = 11.5 Hz, 1H), 3.61 (dd, J = 11.5, 2.9 Hz, 1H), 3.46 (td, J= 11.9, 2.9 Hz, 1H), 3.17 (ddd, J = 19.1, 16.3, 8.1Hz, 3H), 2.85 (s, 3H), 2.64 (d, J = 13.1 Hz, 2H), 2.13 (t, J = 11.8 Hz, 2H), 1.19 (d, J = 6.7 Hz, 3H).

Example 12 Brettphos Pd G3, Cs2COdioxane, 110 °C Step 1. (R)-N-(3-methyl-lH-pyrazol-5-yl)-4-(3-methylmorpholino)-6-(4- (methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (12) WO 2022/002245 PCT/CN2021/104232 id="p-257" id="p-257" id="p-257" id="p-257" id="p-257"

[00257]A mixture of (3R)-4-[2-chloro-6-(4-methanesulfonyloxan-4-yl)pyrimidin-4- yl]-3-methylmorpholine (70 mg, 0.18 mmol), 3-methyl-lH-pyrazol-5-amine (36 mg, 0.37 mmol), BrettPhos Pd G3 (17 mg, 0.02 mmol) and C82CO3 (182 mg, 0.56 mmol) in Dioxane (3 mL) was stirred at 110 °C for 10 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (48 mg, yield: 61%). LC/MS (ESI): m/z 437 [M+H]+. 1H NMR (400 MHz, DMSO) 8 11.78 (s, 1H), 9.(s, 1H), 8.16 (s, 1H), 6.38 (s, 1H), 6.16 (s, 1H), 4.39 (s, 1H), 4.08 (d, J = 13.0 Hz, 1H), 3.98 - 3.84 (m, 3H), 3.72 (d, J = 11.4 Hz, 1H), 3.61 (dd, J = 11.4, 2.9 Hz, 1H), 3.46 (td, J= 11.9, 2.8 Hz, 1H), 3.16 (ddd, J= 19.2, 16.3, 8.1 Hz, 3H), 2.85 (s, 3H), 2.63 (d, J = 13.0 Hz, 2H), 2.24 - 2.02 (m, 5H), 1.19 (d, J = 6.7 Hz, 3H).

Example 13 13-3 13-4 SEM Pd2(dba)3, XantPhosCs2CO3, DioxaneTBAF Step 1. (R)-N-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)methanesulfonamide 88 WO 2022/002245 PCT/CN2021/104232 ( 2 ־ 13 ) id="p-258" id="p-258" id="p-258" id="p-258" id="p-258"

[00258]To a solution of N-(2,6-dichloropyridin-4-yl)methanesulfonamide (500 mg, 2.07 mmol) in NMP (15 mL) was added (3R)-3-methylmorpholine (629 mg, 6.mmol). The mixture was stirred at 170 °C for 1 h under microwave irradiation. LC- MSshowed the reaction was complete. The mixture was diluted with water (60 mL) and extracted with EA (30mL*3) thrice. The combined organic phase was washed with brine, dried over Na2SO4, fdtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to give the desired product (425 mg, yield: 67.02%). LC/MS (ESI): m/z 306 [M+H]+.

Step 2. (R)-N-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)-N-methylmethane sulfonamide (13-3) Mel id="p-259" id="p-259" id="p-259" id="p-259" id="p-259"

[00259]To a mixture of (R)-N-(2-chloro-6-(3-methylmorpholino)pyridin-4- yl)methane sulfonamide (250 mg, 0.82 mmol) and K2CO3 (339 mg, 2.45 mmol) in DMF (8 mL) was added Mel (174 mg, 1.23 mmol). The mixture was stirred at room temperature for 2 h. LC-MS showed the reaction was complete. The reaction mixture was poured into H2O (30 mL) and extracted with EA (30mLx3) thrice. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 1:1, V/V) to give the desired product (218 mg, yield: 83.4%). LC/MS (ESI): m/z 320 [M+H]+.

WO 2022/002245 PCT/CN2021/104232 Step 3. (R)-N-methyI-N-(2-(3-methylmorpholino)-6-((l-((2-(trimethylsilyl)ethoxy) methyI)-lH-pyrazol-5-yI)amino)pyridin-4-yI)methanesulfonamide (13-5) id="p-260" id="p-260" id="p-260" id="p-260" id="p-260"

[00260]To a solution of (R)-N-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)-N- methyl methanesulfonamide (100 mg, 0.31 mmol), l-({[2- (trimethylsilyl)ethoxy]methyl}-XA2-chloranyl)-lH-pyrazol-5-amine (100 mg, 0.mmol) and C82CO3 (306 mg, 0.94 mmol) in dioxane (5 mL) were added Pd2(dba)3 (mg, 0.031 mmol) and XantPhos (36 mg, 0.06 mmol). The mixture was stirred at 1°C for 16 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to give the desired product (118 mg, yield: 76%). LC/MS (ESI): m/z 497 [M+H]+.

Step 4. (R)-N-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl)- N-methylmethanesulfonamide (13) id="p-261" id="p-261" id="p-261" id="p-261" id="p-261"

[00261]A mixture of (R)-N-methyl-N-(2-(3-methylmorpholino)-6-((l-((2-(trimethylsilyl) ethoxy)methyl)-lH-pyrazol-5-yl)amino)pyridin-4-yl )methanesulfonamide (118 mg, 0.24 mmol) in TBAF solution (IM in THE, 2 mL) was stirred at 60 °C for 2 h. LC-MS showed the reaction was complete. The mixture was diluted with H2O and extracted with EA (30mL*3) thrice. The combined organic phase was washed brine, dried over anhydrous Na2SO4, filtered and concentrated to WO 2022/002245 PCT/CN2021/104232 dryness. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (20 mg, yield: 23%). LC/MS (ESI): m/z 367 [M+H]+. 1H NMR (400 MHz, DMSO) 5 8.96 (s, 1H), 7.53 (d, J = 2.2 Hz, 1H), 6.47 (s, 1H), 6.30 (d, J = 2.1 Hz, 1H), 6.05 (d, J = 1.2 Hz, 1H), 4.29 - 4.23 (m, 1H), 3.93 (dd, J = 11.2, 3.2 Hz, 1H), 3.77 -3.71 (m, 2H), 3.64 - 3.61 (m, 1H), 3.50 -3.(m, 1H), 3.19 (s, 3H), 3.07 (dd, J= 12.6, 3.7 Hz, 1H), 3.01 (s, 3H), 1.13 (d, J = 6.Hz, 3H).

Example 14 Step 1. (R)-6-(3-methylmorpholino)-4-(l-(methylsulfonyl)cyclopropyl)-N-(l-((2- (tri-methylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)pyridin-2-amine (14-1) id="p-262" id="p-262" id="p-262" id="p-262" id="p-262"

[00262]To a solution of (R)-4-(6-chloro-4-(l-(methylsulfonyl)cyclopropyl)pyridin-2- yl)-3- methylmorpholine (356.0 mg, 1.08 mmol) and l-({[2- (trimethylsilyl)ethoxy]methyl}-XA2-chloranyl)-lH-pyrazol-5-amine (343.8 mg, 1.mmol) in dioxane (15 mL) were added Pd2(dba)3 (98.5 mg, 0.11 mmol), BrettPhos- Pd-G3 (13.7 mg, 0.015 mmol) and C82CO3 (701.2 mg, 2.15 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =3:1, V/V) to afford the desired product (490 mg , yield: 89 %). LC/MS (ESI) m/z: 508 [M+H]+.

Step 2. (R)-N-methyl-6-(3-methylmorpholino)-4-(l-(methylsulfonyl)cyclopropyl)- 91 WO 2022/002245 PCT/CN2021/104232 N-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)pyridin-2-amine (14-2) id="p-263" id="p-263" id="p-263" id="p-263" id="p-263"

[00263]To solution of (R)-6-(3-methylmorpholino)-4-(l- (methylsulfonyl)cyclopropyl)-N- (l-((2-(trimethylsilyl)ethoxy)m ethyl)-lH-pyrazol-5- yl)pyridin-2-amine (200 mg, 0.39 mmol) in THF (5 mL) at 0 °C was added NaH (60%, 14.2 mg, 0.59 mmol) portion wise. The mixture was stirred at 0 °C for 30 min, then a solution of CH3I (84.0 mg, 0.59 mmol) in THF (1 mL) was added drop wise. The resulting mixture was stirred at room temperature for an additional 1 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (30 mL/2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by column chromatography on silica gel (DCM: MeOH = 50: 1, V/V) to give the desired product (110 mg, yield: 53%). LC/MS (ESI) (m/z): 5[M+H]+.

Step 3. (R)-N-methyl-6-(3-methylmorpholino)-4-(l-(methylsulfonyl)cyclopropyl)- N -(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)pyridin-2-amine (14) id="p-264" id="p-264" id="p-264" id="p-264" id="p-264"

[00264]A mixture of (R)-N-methyl-6-(3-methylmorpholino)-4-(l-(methylsulfonyl)cyclopro- pyl)-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol- 5-yl)pyridin-2-amine (110 mg, 0.21 mmol) in HC1 solution (4M in dioxane, 2 mL) was stirred at room temperature for 2 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under vacuo. The residue was purified by Pre- WO 2022/002245 PCT/CN2021/104232 HPLC (C18, 10-95%, MeCN in H2O with 0.1% HCOOH) to afford the desired product (14 mg, yield: 17%). LC/MS (ESI) m/z: 392 [M+H]+. 1HNMR (400 MHz, DMSO) 5 12.40 (s, 1H), 8.37 (s, 1H), 7.66 (s, 1H), 6.48 (s, 1H), 6.24 (s, 1H), 6.21 (d, J = 1.9 Hz, 1H), 4.27 (d, J = 4.9 Hz, 1H), 3.97 - 3.80 (m, 3H), 3.72 (d, J = 11.2 Hz, 1H), 3.62 (dd, J = 11.3, 2.8 Hz, 2H), 3.53 - 3.42 (m, 3H), 3.05 (td, J = 12.6, 3.6 Hz, 2H), 2.91 (s, 4H), 1.53 (dd, 1 = 6.2, 4.1 Hz, 3H), 1.22 (t, 1 = 5.1 Hz, 3H), 1.14 (d, J = 6.6 Hz, 4H). ethyl formate LDA,THF Example 15 -1 BrettPhos-Pd-G3, Cs2C03 dioxane, 100°C -5 15-6 15 Step 1.2,6-dichloro-4-iodonicotinaldehyde (15-2) Clethyl formate LDA, THF id="p-265" id="p-265" id="p-265" id="p-265" id="p-265"

[00265]To solution of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) in THF (ml) at -78 °C was added LDA solution (2M in THF, 2.74 mL, 5.48 mmol) drop wise. The mixture was stirred at -78 °C for 1 h, following by the addition of ethyl formate (0.44 mL, 5.48 mmol) in THF (1 ml) drop wise. The resulting mixture was stirred at - °C for an additional 2 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA WO 2022/002245 PCT/CN2021/104232 (40 mL><2) twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA = 30:1, V/V) to give the desired product (5mg, yield: 50 %). LC/MS (ESI): m/z 302 [M+H]+.

Step 2.2,6-dichloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)nicotinaldehyde (15-3) id="p-266" id="p-266" id="p-266" id="p-266" id="p-266"

[00266]To a solution of 2,6-dichloro-4-iodopyridine-3-carbaldehyde (1.5 g, 4.mmol) and l,4-dimethyl-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.g, 5.96 mmol) in DME (90 mL) were added Pd(dppf)C12 (360 mg, 0.50 mmol) and Na2CO3 (2.0 M in H2O, 6 mL, 12.0 mmol). The mixture was charged with N2 twice, then stirred at 100 °C overnight under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with H2O (100 mL) and extracted with EA (100 mLx2) twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA= 10:1, V/V) to give the desired product (548 mg, yield: 41 %). LC/MS (ESI): m/z 270 [M+H]+. 1H NMR (4MHz, DMSO) 5 9.98 (s, 1H), 7.79 (s, 1H), 131 (s, 1H), 3.59 (s, 3H), 1.79 (s, 3H).

Step 3. (R)-2-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-(3-methylmorpholino) nicotinaldehyde (15-4) WO 2022/002245 PCT/CN2021/104232 id="p-267" id="p-267" id="p-267" id="p-267" id="p-267"

[00267]A solution of 2,6-dichloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)pyridine-3- carbaldehyde (330 mg, 1.22 mmol) and (3R)-3-methylmorpholine (185 mg, 1.mmol) in NMP (14 mL) was stirred at 130 °C for 1 h under microwave irradiation. LC-MSshowed the reaction was complete. The reaction mixture was quenched with H2O (40 mL) and extracted with EA (50 mLx2) twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA= 5:1, V/V) to give the desired product (142 mg, yield: 35 %). LC/MS (ESI): m/z 3 [M+H]+.

Step 4. (R)-(2-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yI)-6-(3-methyImorpholino) pyridin-3-yl)methanol (15-5) id="p-268" id="p-268" id="p-268" id="p-268" id="p-268"

[00268]To a solution of 2-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-[(3R)-3-methyl morpholin-4-yl]pyridine-3-carbaldehyde (140 mg, 0.42 mmol) in THE (4 mL) was added NaBH4 (14 mg, 0.42 mmol). The resulting mixture was stirred at 0 °C for 0.5 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with H2O and extracted with EA (40 mL^2) twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA= 3:1, V/V) to give the desired product (140 mg, yield: 99 %). LC/MS (ESI): m/z 337 [M+H]+.

Step 5. (R)-(4-(l,4־dimethyl-lH-pyrazol-5-yl)-6-(3-methylmorpholino)-2-((l-((2- (trimethylsilyl)ethoxy)methyI)-lH-pyrazol-5-yl)amino)pyridin-3-yI)methanol (15- 6) WO 2022/002245 PCT/CN2021/104232 BrettPhos-Pd-G 3, Cs2COdioxane, 100°C id="p-269" id="p-269" id="p-269" id="p-269" id="p-269"

[00269]A mixture of [2-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-[(3R)-3- methylmorpholin-4-yl]pyridin-3-yl]methanol (135 mg, 0.40 mmol), l-({[2- (trimethyl silyl)ethoxy] methyl }-Z/ 2-chloranyl)-1 H-pyrazol-5-amine (128 mg, 0.mmol), BrettPhos-Pd-G3 (36 mg, 0.04 mmol) and Cs2CO3 (392 mg, 1.20 mmol) in dioxane (6 mL) was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA= 1:1, V/V) to give the desired product (46 mg, yield: 22 %). LC/MS (ESI): m/z 5[M+H]+.

Step 6. (R)-(2-((lH-pyrazol-5-yl)amino)-4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-(3- methylmorpholino)pyridin-3-yl)methanol (15) id="p-270" id="p-270" id="p-270" id="p-270" id="p-270"

[00270]A mixture of [4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-[(3R)-3-methylmorpholin- 4-yl]-2-{[l-({[2-(trimethylsilyl)ethoxy]methyl}-XA2-chloranyl)-lH-pyrazol-5- yl]amino}pyridin-3-yl]methanol (46 mg, 0.09 mmol) in TBAF solution (1.0 M in THF, 5 mL, 5.0 mmol) was stirred at 40 °C overnight. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (C18, 10-95% acetonitrile in H2O with 0.1% ammonia) to give the desired product (13.2 mg, 38%). LC/MS (ESI) m/z: 384 [M+H]+. 1HNMR96 WO 2022/002245 PCT/CN2021/104232 (400 MHz, DMSO) 3 12.16 (s, 1H), 8.51 (s, 1H), 7.59 (s, 1H), 7.32 (s, 1H), 6.55 (s, 1H), 5.89 (s, 1H), 5.38 (s, 1H), 4.26 (s, 1H), 4.22 - 4.14 (m, 2H), 3.96 -3.90 (m, 1H), 3.85 - 3.78 (m, 1H), 3.72 (d, J= 11.3 Hz, 1H), 3.64 (d, J= 2.6 Hz, 1H), 3.61 (d, J= 2.9 Hz, 1H), 3.58 (d, J= 1.6 Hz, 3H), 3.10-3.03 (m, 1H), 1.85 (s, 3H), 1.14 (dd, J= 6.6, 3.0 Hz, 3H).

Example 16 Step 1. methyl 2,6-dichloro-4-methylpyridine-3-carboxylate (17-2) COOH id="p-271" id="p-271" id="p-271" id="p-271" id="p-271"

[00271]To a solution of 2,6-di chi oro-4-methylpyridine-3-carboxylic acid (500 mg, 2.43 mmol) in DMF (10 mL) were added CHI (0.3 mL, 4.85 mmol) and K:CO3 (5mg, 3.64 mmol). The mixture was stirred at room temperature overnight. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 10:1, V/V) to give the desired product (525 mg, yield: 98%). LC/MS (ESI): m/z 220 [M+H]+.

Step 2. methyl 4-(bromomethyl)-2,6-dichloropyridine-3-carboxylate (17-3) WO 2022/002245 PCT/CN2021/104232 id="p-272" id="p-272" id="p-272" id="p-272" id="p-272"

[00272]To a solution of methyl 2,6-dichloro-4-methylpyridine-3-carboxylate (1 g, 4.54 mmol) in CC14 (40 mL) were added MBS (0.97 g, 5.45 mmol) and AIBN (mg, 0.45 mmol). The mixture was stirred at 80 °C overnight. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with saturated Na2S2O3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA= 10:1, V/V) to give the desired product (1.g, yield: 76%). LC/MS (ESI): m/z 300 [M+H]+.

Step 3. methyl 2,6-dichloro-4-(methanesulfonylmethyl)pyridine-3-carboxylate ( 4 ־ 17 ) id="p-273" id="p-273" id="p-273" id="p-273" id="p-273"

[00273]To a solution of methyl 4-(bromomethyl)-2,6-dichloropyridine-3-carboxylate (600 mg, 2.00 mmol) in DMF (20 mL) were added sodium methanesulfmate (4mg, 4.01 mmol) The mixture was stirred at room temperature for 2 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA =5:1, V/V) to give the desired product (510 mg, yield: 85%). LC/MS (ESI): m/z 298 [M+H]+.

Step 4. methyl 2-chloro-4-(methanesulfonylmethyl)-6-[(3R)-3-methylmorpholin- 4־yl] pyridine-3-carboxylate (17-6) WO 2022/002245 PCT/CN2021/104232 id="p-274" id="p-274" id="p-274" id="p-274" id="p-274"

[00274]To a solution methyl 2,6-dichloro-4-(methanesulfonylmethyl) pyridine-3- carboxylate (300 mg, 1.01 mmol ) in NMP (9 mL) was added (3R)-3- methylmorpholine (204 mg, 2.01 mmol). The mixture was stirred at 120 °C for 1 h under microwave irradiation. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA= 3:1, V/V) to give the desired product (150 mg, yield: 41 %). LC/MS (ESI): m/z 363 [M+H]+.

Step 5. Methyl 2-chloro-4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3- methylmorpholin-4-yl]pyridine-3-carboxylate (17-7) 50% NaOHTBAB, Toluene id="p-275" id="p-275" id="p-275" id="p-275" id="p-275"

[00275]To a solution of methyl 2-chloro-4-(methanesulfonylmethyl)-6-[(3R)-3- methyl morpholin-4-yl]pyridine-3-carboxylate (150 mg, 0.41 mmol) in Toluene (mL) were added TBAB (27 mg, 0.08 mmol), 1 2-dibromoethane (233 mg, 1.24 mmol) and NaOH aqueous solution (10 M, 0.41 mL, 4.13 mmol). The mixture was stirred at °C for 6 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 3:1, V/V) to give the desired product (1mg, yield: 62 %). LC/MS (ESI): m/z 389 [M+H]+.

WO 2022/002245 PCT/CN2021/104232 Step 6. [2-chloro-4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin- 4-yl] pyridin-3-yl] methanol (17-8) id="p-276" id="p-276" id="p-276" id="p-276" id="p-276"

[00276]To a solution of methyl 2-chloro-4-(l-methanesulfonyl cyclopropyl)-6-[(3R)- 3-methyl morpholin-4-yl]pyridine-3-carboxylate (200 mg, 0.51 mmol) in THF (mL) were added LiBH4 (2M in THF, 1.03 mL, 2.06 mmol). The mixture was stirred at room temperature overnight. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA= 1:1, V/V) to give the desired product (150 mg, yield: 80 %). LC/MS (ESI): m/z 361 [M+H]+.

Step 7. (R)-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)-4-(l- (methylsulfo- nyl)cyclopropyl)pyridin-3-yl)methanol (17) id="p-277" id="p-277" id="p-277" id="p-277" id="p-277"

[00277]To a solution of (R)-(2-chloro-6-(3-methylmorpholino)-4-(l- (methylsulfonyl)cyclo propyl)pyridin-3-yl)methanol (50 mg, 0.14 mmol) and 1H- pyrazol-5-amine (23 mg, 0.28 mmol) in dioxane (2 mL) were added Brettphos-Pd-G(12.5 mmol, 0.014 mmol) and Cs2CO3 (135 mg, 0.41 mmol). The mixture was stirred at 110 °C overnight under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine,100 WO 2022/002245 PCT/CN2021/104232 dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (14 mg, yield: 24%). LC/MS (ESI): m/z 408 [M+H]+. 1HNMR (4MHz, DMSO) 5 12.11 (s, 1H), 8.52 (d, J=4.3 Hz, 1H), 7.56 (d,J= 1.6 Hz, 1H), 6.(s, 1H), 6.25 (s, 1H), 5.30 (s, 1H), 4.89 (d, J= 13.3 Hz, 1H), 4.35 (d, J= 12.8 Hz, 1H), 4.29 (s, 1H), 3.94 (d, J= 8.4 Hz, 1H), 3.77 (dd, J =25.7, 11.3 Hz, 2H), 3.65 (s, 2H), 3.08 (d, J= 11.5 Hz, 1H), 2.96 (s, 3H), 1.84 (s, 1H), 1.49 (d, J= 28.1 Hz, 2H), 1.33 (s, 1H), 1.13 (dd, J= 18.8, 5.4 Hz, 3H). 1-7 Example 17 19-2 19 Step 1. tert-butyl 5-{[4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3- methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate ( 2 ־ 19 ) id="p-278" id="p-278" id="p-278" id="p-278" id="p-278"

[00278]A mixture of (3R)-4-[6-chloro-4-(l-methanesulfonylcyclopropyl)pyridin-2- yl]-3-methylmorpholine (450 mg, 1.36 mmol), tert-butyl 5-amino-3-methyl-lH- pyrazole-1-carboxylate (402 mg, 2.04 mmol), BrettPhos-Pd-G3 (27 mg, 0.03 mmol) and C82CO3 (1.1 g, 3.40 mmol) in dioxane (40 mL) was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column 101 WO 2022/002245 PCT/CN2021/104232 chromatography on silica gel (PE : EA = 1:1, V/V) to give the desired product (5mg, yield: 79%). LC/MS ESI (m/z): 492 [M+H]+.

Step 2. 4-(l-methanesulfonylcyclopropyl)-N-(3-methyl-lH-pyrazol-5-yl)-6-[(3R)- 3-methylmorpholin-4-yl]pyridin-2-amine (19) id="p-279" id="p-279" id="p-279" id="p-279" id="p-279"

[00279]A mixture of tert-butyl 5-{[4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3- methyl morpholin-4-yl]pyridin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate (526 mg, 1.07 mmol) in HC1 solution (4 M in dioxane, 8 mL) was stirred at room temperature overnight. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (213 mg, yield: 51%). LC/MS ESI (m/z): 392 [M+H]+. 1HNMR (400 MHz, DMSO) 11.69 (s, 1H), 8.79 (s, 1H), 6.66 (s, 1H), 6.18 (s, 1H), 6.00 (s, 1H), 4.26 (d, J - 6.6 Hz, 1H), 3.93 (dd, J= 11.2, 3.2 Hz, 1H), 3.81 (d, J= 11.1 Hz, 1H), 3.72 (d, J = 11.2 Hz, 1H), 3.61 (dd, J= 11.3, 2.8 Hz, 1H), 3.47 (dd, J = 11.6, 8.9 Hz, 1H), 3.04 (td, J = 12.5, 3.6Hz, 1H), 2.93 (s, 3H), 2.17 (s, 3H), 1.56 (dd, J - 5.7, 3.9Hz, 2H), 1.24 (dd, J - 6.2, 4.7 Hz, 2H), 1.13 (d, J = 6.6 Hz, 3H).

Example 18 102 WO 2022/002245 PCT/CN2021/104232 -1 LDA, CHal Boc 20-7 1) Brettphos Rd G32) HCI/Dioxane Step 1.2,6-dichloro-4-iodo-3-methylpyridine (20-2) id="p-280" id="p-280" id="p-280" id="p-280" id="p-280"

[00280]To a solution of 2,6-dichloro-3-iodopyridine (2 g, 7.30 mmol) in DMF (mL) at -60 °C was added LDA (2M in THF, 5.48 mL, 10.95 mmol) drop wise. The mixture was stirred at -60 °C for 1 h, then iodomethane (0.68 mL, 10.95 mmol) was added drop wise. The resulting mixture was stirred at -60 °Cfor an additional 1 h. LC- MS showed the reaction was complete. The reaction was quenched with saturated NH4Cl aqueous solution, and extracted with EA (50 mL). The organic layer was separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE : EA= 10:1, V/V) to afford the desired product (1.7 g, yield: 81%). LC/MS (ESI): m/z 288 [M+H]+.

Step 2. (R)-4-(6-chloro-4-iodo-5-methylpyridin-2-yl)-3-methylmorpholine (20-4) 103 WO 2022/002245 PCT/CN2021/104232 id="p-281" id="p-281" id="p-281" id="p-281" id="p-281"

[00281]To a solution of 2,6-dichloro-4-iodo-3-methylpyridine (1.7 g, 5.90 mmol) in NMP (17.0 mL) were added (R)-3-methylmorpholine (1.79 g, 17.71 mmol) andN,N- Diisopropylethylamine (2.93 mL, 17.71 mmol). The mixture was stirred at 180 °C for h under microwave irradiation. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE : EA =3:1, V/V) to afford the desired product (7mg, yield: 36%). LC/MS (ESI): m/z 353 [M+H]+.

Step 3. (R)-4-(6-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5-methylpyridin-2- yl)-3-methylmorpholine (20-6) id="p-282" id="p-282" id="p-282" id="p-282" id="p-282"

[00282]To a solution of (R)-4-(6-chloro-4-iodo-5-methylpyridin-2-yl)-3- methylmorpholine (600 mg, 1.70 mmol) in DMF (6 mL) were added 1,4-dimethyl- 1H-I,2,3־triazole (182 mg, 1.87 mmol), Tetramethylammonium acetate (272 mg, 2.mmol) and Bis(triphenylphosphine)palladium(II) chloride (132 mg, 0.17 mmol). The mixture was stirred at 140 °C for 5 h under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE : EA =1:1, V/V) to afford the desired product (400 mg, yield: 73%). LC/MS (ESI): m/z 322 [M+H]+. 104 WO 2022/002245 PCT/CN2021/104232 Step 4. (R)-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yI)-3-methyI-6-(3- methyImorpholino)-N-(lH-pyrazol-5-yl)pyridin-2-amine (20) 1) Brettphos Pd G32) HCI/Dioxane id="p-283" id="p-283" id="p-283" id="p-283" id="p-283"

[00283]To a solution of (R)-4-(6-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5- methyl pyridin-2-yl)-3-methylmorpholine (100 mg, 0.31 mmol) in Dioxane (2 mL) were added tert-butyl 5-amino-lH-pyrazole-l-carboxylate (85 mg, 0.47 mmol), C82CO3 (203 mg, 0.62 mmol) and BrettPhos-Pd-G3 (28 mg, 0.03 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in DCM (5 mL), then HC1 solution (4M in dioxane, 2 mL) was added. The resulting mixture was stirred at room temperature for 1211 LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to dryness. The residue was purified by Pre-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to afford the desired product (10 mg, yield: 8.7%). LC/MS (ESI): m/z 369 [M+H]+. HNMR (400 MHz, DMSO) 8 8.13 (s, 1H), 7.56 (s, 1H), 6.46 (s, 1H), 5.97 (s, 1H), 4.24-4.14 (m, 1H), 3.90 (dd, J= 11.2, 3.1 Hz, 1H), 3.79 (s, 3H), 3.77- 3.71 (m, 1H), 3.69 (d, J =11.5 Hz, 1H), 3.61 (d, J = 10.8Hz, 1H), 3.46 (d, J = 2.6 Hz, 1H), 3.02 (t, J =12.5 Hz, 1H), 2.10 (s, 3H), 1.82 (d, J = 0.8 Hz, 3H), 1.11 (d, J = 6.Hz, 3H).

Example 19 105 WO 2022/002245 PCT/CN2021/104232 1) Brettphos Pd G3 2) HCI/Dioxane -6 21 Step 1. (R)-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-3-methyl-N-(3-methyl-lH- pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-2-amine (21) 1) Brettphos Pd G32) HCI/Dioxane id="p-284" id="p-284" id="p-284" id="p-284" id="p-284"

[00284]To a solution of (R)-4-(6-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5- methyl pyridin-2-yl)-3-methylmorpholine (100 mg, 0.31 mmol) in dioxane (2 mL) were added 3-methyl-lH-pyrazol-5-amine (45 mg, 0.47 mmol), C82CO3 (203 mg, 0.62 mmol) and BrettPhos-Pd-G3 (28 mg, 0.03 mmol). The mixture was stirred at 1°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in DCM (5 mL), then HC1 solution (4M in dioxane, 2 mL) was added. The resulting mixture was stirred at room temperature for 12h. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to dryness. The residue was purified by Pre-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to afford the desired product (15 mg, yield: 12.6%). LC/MS (ESI) m/z: 383 [M+H]+. IHNMR (400 MHz, DMSO) 5 8.00 (s, 1H), 6.22 (s, 1H), 5.96 (s, 1H), 4.20 (s, 1H), 3.91 (dd, J - 11.2, 3.1Hz, 1H), 3.78 (s, 3H), 3.77 - 3.72 (m, 1H), 3.70 (d, J = 11.8 Hz, 1H), 3.(d, J = 10.8 Hz, 1H),3.5O - 3.43 (m, 1H), 3.06 - 2.98 (m, 1H), 2.20 (s, 3H), 2.09 (s, 3H), 1.80 (d, J = 0.7 Hz, 3H), 1.12 (d, J = 6.6 Hz, 3H).

Example 20 106 WO 2022/002245 PCT/CN2021/104232 22-1 22-2 Pd(dppf)CI2, Na2CO3,di0xane/H2O Step 1: (R)-4-(4,6-dichloropyridin-2-yl)-3-methylmorpholine (22-2) id="p-285" id="p-285" id="p-285" id="p-285" id="p-285"

[00285]To a solution of 2,6-dichloro-4-iodopyridine (800 mg, 2.92 mmol) and (R)-3- methylmorpholine (325 mg, 3.21 mmol) in DMA (8 mL) were added DIEA(755 mg, 5.84 mmol). The mixture was charged with N2 twice, then stirred at 120 °C for 12 hrs. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, fdtered and concentrated in vacuo The resulting mixture was purified by flash chromatography eluting with PE/EtOAc (20:1, 8:1) to afford the desired product (500 mg, yield: 68.9%).

Step 2: (R)-4-(6-chloro-4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)-3- methylmorpholine (22-3) id="p-286" id="p-286" id="p-286" id="p-286" id="p-286"

[00286]To a solution of (R)-4-(6-chloro-4-iodopyridin-2-yl)-3-methylmorpholine (300 mg, 1.21mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoxazole (270.8 mg, 1.21 mmol) in dioxane (10 mL) were added Na2CO3 (320 mg, 3.03 mmol) and Pd(dppf)C12 (88 mg, 0.12 mmol). The mixture was charged withN 107 WO 2022/002245 PCT/CN2021/104232 twice, then stirred at 90 °C for 12 hrs. The reaction mixture was diluted with water (mL) and extracted with EA (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting mixture was purified by flash chromatography eluting with PE/EtOAc (3:1, 1:1) to afford the desired product (320 mg, yield: 86.02%).

Step 3: (R)-4-(3,5-dimethylisoxazol-4-yl)-6-(3-methylmorpholino)-N-(lH-pyrazol- 5-yl)pyridin-2-amine (22) id="p-287" id="p-287" id="p-287" id="p-287" id="p-287"

[00287]To a (R)-4-(6-chloro-4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)-3- methylmorpholine (150 mg, 0.49 mmol) and tert-butyl 5-amino-lH-pyrazole-l- carboxylate (108 mg, 0.59 mmol) in dioxane (8 mL) were added C82CO3 (400 mg, 1.23 mmol) and BrettPhos Pd G3 (45 mg, 0.049 mmol). The mixture was charged with N2 twice, then stirred at 90 °C overnight. The reaction was diluted with water and extracted with EtOAc (30 mL*2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Pre-TLC (DCM/MeOH=10/l) to afford the desired product (20 mg, yield 11.49 %). LC/MS (ESI) m/z: 355.0 [M+H]+. id="p-288" id="p-288" id="p-288" id="p-288" id="p-288"

[00288]1H NMR (400 MHz, DMSO-d6) 5 ppm 12.03 (br s, 1 H) 8.98 (br s, 1 H) 7.(br s, 1 H) 6.33 - 6.47 (m, 2 H) 5.99 (s, 1 H) 4.30 (br d, 1=5.16 Hz, 1 H) 3.94 (br dd, 1=11.12, 3.20 Hz, 1 H) 3.84 (br d, 1=11.68 Hz, 1 H) 3.71 - 3.75 (m, 1 H) 3.61 - 3.(m, 1 H) 3.45 - 3.52 (m, 1 H)3.03 -3.10(m, 1 H) 2.44 (s, 3 H) 2.25 (s, 3 H) 1.15 (d, 1=6.64 Hz, 3 H).

Example 21 108 WO 2022/002245 PCT/CN2021/104232 Step 1. (3R)-4-(6-chloro-4-iodopyridin-2-yl)-3-methylmorpholine (23-3) id="p-289" id="p-289" id="p-289" id="p-289" id="p-289"

[00289]To a solution of2,6-dichloro-4-iodopyridine (500 mg, 1.83 mmol) inNMP (10 mL) were added (3R)-3-methylmorpholine (554.1 mg, 5.48 mmol). The mixture was stirred at 150 °C for 1 h under microwave irradiation. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 10:1, V/V) to give the desired product (2mg, yield: 40 %). LC/MS (ESI): m/z 339 [M+H]+.

Step 2. (3R)-4-[6-chloro-4-(dimethyl-lH-l,2,3-triazol-5-yl)pyridin-2-yl]-3-methyl morpholine (23-5) id="p-290" id="p-290" id="p-290" id="p-290" id="p-290"

[00290]To a solution of (3R)-4-(6-chloro-4-iodopyridin-2-yl)-3-methylmorpholine (300 mg, 0.88 mmol) and l,4-dimethyl-lH-l,2,3-triazole (103.3 mg, 1.06 mmol) in DMF (15 mL) were added Pd(PPh3)2C12 (62.2 mg, 0.09 mmol) andtetramethylammonium acetate (141.6 mg, 1.06 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was109 WO 2022/002245 PCT/CN2021/104232 complete. The reaction mixture was diluted with DCM (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA =3:1, V/V) to give the desired product (210 mg, yield: 77 %). LC/MS (ESI): m/z 3[M+H]+.

Step 3. 4-(dimethyl-lH-l,2,3-triazol-5-yl)-N-(3-methyl-lH-pyrazol-5-yl)-6-[(3R)-3 -methylmorpholin-4-yl] pyridin-2-amine (23) id="p-291" id="p-291" id="p-291" id="p-291" id="p-291"

[00291]To a solution of (3R)-4-[6-chloro-4-(dimethyl-lH-l,2,3-triazol-5-yl)pyridin- 2-yl]-3-methylmorpholine (90 mg, 0.29 mmol) in dioxane (2 mL) were added tert- butyl 5-amino-3-methyl-lH-pyrazole-l-carboxylate (86.51 mg, 0.439 mmol), BrettPhos-Pd -G3 (26.5 mg, 0.03 mmol) and C82CO3 (190.5 mg, 0.59 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (Cl 8, 10-95% MeCN in H2O with 0.1% ammonia) to give the desired product (35 mg, yield: 32 %). LC/MS (ESI): m/z 369 [M+H]+. LHNMR(400 MHz, DMSO) 6 11.71 (s, 1H), 8.92 (s, 1H), 6.55 (s, 1H), 6.07 (d, J= 6.1 Hz, 2H), 4.31 (d, J = 5.9 Hz, 1H), 3.96 (s, 3H), 3.90 (dd, J = 14.1, 8.1 Hz, 2H), 3.72 (d, J= 11.2 Hz, 1H), 3.63 (dd, J= 11.2, 2.9 Hz, 1H), 3.48 (td, J= 11.8, 2.8 Hz, 1H), 3.07 (td, J= 12.5, 3.5 Hz, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.(d,T= 6.6 Hz, 3H).

Example 22 110 WO 2022/002245 PCT/CN2021/104232 Step 1. (R)-2-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl)- 2-methylpropanenitrile (24) id="p-292" id="p-292" id="p-292" id="p-292" id="p-292"

[00292]To a solution of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}- 2-methylpropanenitrile (60 mg, 0.21 mmol) and lH-pyrazol-5-amine (35 mg, 0.mmol) in Dioxane (3 mL) were added BrettPhos-Pd-G3 (19 mg, 0.21 mmol) and C82CO3 (210 mg, 0.64 mmol). The mixture was stirred at 110 °C for 10 h under Natmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (C18, 10- 95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (60 mg, yield: 85%). LC/MS (ESI): m/z 327 [M+H]+. 1HNMR (400 MHz, DMSO) 5 12.10 (s, 1H), 9.02 (s, 1H),7.53 (d, J = 2.2 Hz, 1H), 6.59 (s, 1H), 6.30 (d, J = 1.9 Hz, 1H), 6.08 (d, J = 1.0 Hz, 1H), 4.32 (d, J = 6.5 Hz, 1H), 3.93 (dd, J = 11.2, 3.3 Hz, 1H), 3.79 (d, J = 12.8 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 3.62 (dd, J = 11.3, 2.9 Hz, 1H), 3.47 (td, J = 11.8, 3.0 Hz, 1H), 3.06 (td, J= 12.6, 3.7 Hz, 1H), 1.63 (s, 6H), 1.13 (d, J = 6.6 Hz, 3H).

Example 23 111 WO 2022/002245 PCT/CN2021/104232 Mel, f-BuONar THF -2 25-3 Step 1. 2- {2-chloro-6- [(3R)-3-methylmor pholin-4-yl] pyridin-4-yl}-2- methylpropane nitrile (25-2) id="p-293" id="p-293" id="p-293" id="p-293" id="p-293"

[00293]To a solution of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl} acetonitrile (173 mg, 0.69 mmol) in THF (6 mL) at 0 °C was added Sodium tert- butoxide (198 mg, 2.06 mmol) and iodomethane (0.13 mL, 2.06 mmol). The mixture was stirred at ambient temperature overnight. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =3:1, V/V) to give the desired product (154 mg, yield: 80%). LC/MS ESI (m/z): 280 [M+H]+.

Step 2. tert-butyl 5-{[4-(l-cyano-l-methylethyl)-6-[(3R)-3-methylmorpholin-4- yl]pyridin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate (25-3) BrettPhos-Pd-G 3, Cs2COdioxane, 100°C id="p-294" id="p-294" id="p-294" id="p-294" id="p-294"

[00294]To a solution of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}-2-methyl propanenitrile (154 mg, 0.55 mmol) and tert-butyl 5-amino-3-methyl-lH- pyrazole-1-carboxylate (163 mg, 0.83 mmol) in dioxane (10 mL) were added112 WO 2022/002245 PCT/CN2021/104232 BrettPhos-Pd-G3 (50 mg, 0.06 mmol) and Cs2CO3 (538 mg, 1.65 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to give the desired product (156 mg, yield: 64%). LC/MS ESI (m/z): 441 [M+H]+.

Step 3. 2-methyl-2-{2-[(3-methyl-lH-pyrazol-5-yl)amino]-6-[(3R)-3-methyl morpholin-4-yl] pyridin-4-yl} propanenitrile (25) id="p-295" id="p-295" id="p-295" id="p-295" id="p-295"

[00295]A mixture of tert-butyl 5-{[4-(l-cyano-l-methylethyl)-6-[(3R)-3- methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate (1mg, 0.35 mmol) in HC1 solution (4 M in dioxane, 4 mL) was stirred at room temperature overnight. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (88.5 mg, yield: 73%). LC/MS ESI (m/z): 341 [M+H]+. 1HNMR (400 MHz, DMSO) 9.43 (s, 1H), 6.60 (s, 1H), 6.18 (s, 1H), 6.04 (s, 1H), 4.30 (dd, J = 6.6, 1.9 Hz, 1H), 3.95 (dd, J = 11.3, 3 4 Hz, 1H), 3.80 (dd, J = 13.1, 2.0 Hz, 1H), 3 74 (d, J =11.3 Hz, 1H), 3.64 (dd, J = 11.3, 2.8 Hz, 1H), 3.49 (td, J = 11.8, 3.0 Hz, 1H), 3.11 (td, J = 12.6, 3.8 Hz, 1H), 2.21 (s, 3H), 1.64 (s, 6H), 1.15 (d, J = 6.6 Hz, 3H).

Example 24 1-6 26-1 26-3 26 Step 1. (R)-4-(6-chloro-4-(2-(methylsulfonyl)propan-2-yl)pyridin-2-yl)-3-methyl 113 WO 2022/002245 PCT/CN2021/104232 morpholine (26-1) id="p-296" id="p-296" id="p-296" id="p-296" id="p-296"

[00296]To a solution of (3R)-4-[6-chloro-4-(methanesulfonylmethyl)pyridin-2-yl]-3- methyl morpholine (5.8 g, 19.03 mmol) in THF (100 mL) were added CHI (4.7 mL, 76.11 mmol) and t-BuONa (7.31 g, 76.11 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with EA (100 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA=1:1, V/V) to give the desired product (5.3 g, yield: 83.7%). LC/MS (ESI): m/z 333 [M+H]+ Step 2. 6-((R)-3-methylmorpholino)-4-(2-(methylsulfonyl)propan-2-yl)-N-(l- (tetra hydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)pyridin-2-amine (26-3) Brettphos Pd G3 id="p-297" id="p-297" id="p-297" id="p-297" id="p-297"

[00297]To a solution of (3R)-4-[6-chloro-4-(2-methanesulfonylpropan-2-yl)pyridin- 2-yl]-3-methylmorpholine (4.0 g, 12.02 mmol) in Dioxane (80 mL) were added 1- (oxan-2-yl)-lH-pyrazol-5-amine (3.0 g, 18.03 mmol), Brettphos Pd G3 (1.09 g, 1.mmol), and C82CO3 (11.8 g, 36.05 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. The reaction was diluted with DCM (1mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH=30:1, V/V) to give the desired product (4.45 g, yield: 80%). LC/MS (ESI): m/z 464 [M+H]+ 114 WO 2022/002245 PCT/CN2021/104232 Step 3. (R)-6-(3-methylmorpholino)-4-(2-(methylsulfonyl)propan-2-yl)-N-(lH- pyrazol-5-yl)pyridin-2-amine (26) id="p-298" id="p-298" id="p-298" id="p-298" id="p-298"

[00298]To a solution of 4-(2-methanesulfonylpropan-2-yl)-6-[(3R)-3- methylmorpholin-4-yl]-N-[l-(oxan-2-yl)-lH-pyrazol-5-yl]pyridin-2-amine (4.45 g, 9.60 mmol) in DCM (50 mL) were added HCl/dioxane (50 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuo. The residue was diluted with DCM (50 mL), then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (2.08 g, 57 %). LC/MS (ESI): m/z 380 [M+H]+. 1H NMR (400 MHz, DMSO) 5 12.02 (s, 1H), 8.95 (s, 1H), 7.53 (s, 1H), 6.65 (s, 1H), 6.27 (d, J= 60.7 Hz, 1H), 6.19 (s, 1H), 4.28 (d,J=6.2Hz, 1H), 3.94 (dd, J = 11.1, 3.2 Hz, 1H), 3.76 (dd, J = 22.8, 11.2 Hz, 2H), 3.63 (dd, J = 11.2, 2.8 Hz, 1H), 3.48 (td, J= 11.7, 2.9 Hz, 1H), 3.05 (td, J= 12.6, 3.7 Hz, 1H), 2.76 (s, 3H), 1.66 (s, 6H), 1.12 (d, J= 6.6 Hz, 3H).

Example 25 BrettPhos-Pd-G 3, Cs2COdioxane, 10C°CHCl/dioxane 26-1 27-1 Step 1. tert-butyl 5-{[4-(2-methanesulfonylpropan-2-yl)-6-[(3R)-3-methyl morpholin-4-yl]pyridin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate (27-1) 115 WO 2022/002245 PCT/CN2021/104232 id="p-299" id="p-299" id="p-299" id="p-299" id="p-299"

[00299]A mixture of (3R)-4-[6-chloro-4-(2-methanesulfonylpropan-2-yl)pyridin-2- yl]-3-methylmorpholine (580 mg, 1.74 mmol), tert-butyl 5-amino-3-methyl-lH- pyrazole-1-carboxylate (516 mg, 2.61 mmol), BrettPhos-Pd-G3 (157.9 mg, 0.mmol) and C82CO3 (1.42 g, 4.36 mmol) in dioxane (20 mL) was stirred at 100 °C overnight under nitrogen atmosphere LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to give the desired product (7mg, yield: 88%). LC/MS ESI (m/z): 494 [M+H]+.

Step 2. 4-(2-methanesulfonylpropan-2-yl)-N-(3-methyl-lH-pyrazol-5-yl)-6-[(3R)- 3-methylmorpholin-4-yl] pyridin-2-amine (27) id="p-300" id="p-300" id="p-300" id="p-300" id="p-300"

[00300]A mixture of tert-butyl 5-{[4-(2-methanesulfonylpropan-2-yl)-6-[(3R)-3- methyl morpholin-4-yl]pyridin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate (758 mg, 1.54 mmol) in HC1 solution (4 M in dioxane, 8 mL) was stirred at ambient temperature overnight. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (215 mg, yield: 35%). LC/MS ESI (m/z): 394 [M+H]+. 1HNMR (400 MHz, DMSO) 11.67 (s, 1H), 8.79 (s, 1H), 6.70 (s, 1H), 6.19 (s, 1H), 6.03 (s, 1H), 4.27 (d, J = 6.6 Hz,116 WO 2022/002245 PCT/CN2021/104232 1H), 3.94 (dd, J = 11.2, 3.2 Hz, 1H), 3.79 (d, 1=13.1 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 3.63 (dd, J = 11.2, 2.8 Hz, 1H), 3.48 (td, J = 11.8, 2.9 Hz, 1H), 3.04 (td, J = 12.6, 3.7 Hz, 1H), 2.75 (s, 3H), 2.17 (s, 3H), 1.66 (s, 6H), 1.12 (d, J = 6.6 Hz, 3H).

Example 26 BrettPhos Rd G3, Cs2COdioxane, 110 °C Step 1. (R)-2-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4- yl)-2-methylpropanenitrile (28) id="p-301" id="p-301" id="p-301" id="p-301" id="p-301"

[00301]A mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}- 2-methyl propanenitrile (100 mg, 0.35 mmol), lH-pyrazol-5-amine (59 mg, 0.mmol), BrettPhos Pd G3 (32 mg, 0 03 mmol) and C82CO3 (349 mg, 1.07 mmol) in dioxane (4 mL) was stirred at 110 °C for 16 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (36 mg, yield: 31%). LC/MS (ESI): m/z 328 [M+H]+. 1H NMR (400 MHz, DMSO) 5 12.08 (s, 1H), 9.20 (s, 1H), 8.13 (s, 1H), 7.51 (s, 1H), 6.52 (s, 1H), 6.25 (s, 1H), 4.41 (s, 1H), 4.01 (d, J = 12.8 Hz, 1H), 3.93 (dd, J= 11.3, 3.4 Hz, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.58 (dd, J= 11.4, 3.0 Hz, 1H), 3.43 (td, J = 11.8, 2.9 Hz, 1H), 3.14 (td, J = 13.0, 3.8 Hz, 1H), 1.65 (s, 6H), 1.(d, J = 6.7 Hz, 3H).117 WO 2022/002245 PCT/CN2021/104232 Example 27 PdCI2(dppf), Na2CO3DMBH2O, 90 °CPd2(dba)3l Xant-Phos Cs2CO3؛ dixoane, 100 °C Pd2(dba)3, Ru-Phos Cs2CO3؛ dixoane, 100 °CTBAF/THF, 70 °C Step 1.2,6-dichloro-3-fluoro-4-iodopyridine (33-2) id="p-302" id="p-302" id="p-302" id="p-302" id="p-302"

[00302]To a solution of 2,6-dichloro-3-fluoropyridine (2.0 g, 12.05 mmol) in anhydrous THF (30 mL) at -78 °C was added LDA (2.0 M in THF, 6.6 mL, 13.mmol) drop wise under N2 atmosphere. The mixture was stirred at -78 °C for 1 h, then a solution of 12 (4.0 g, 15.74 mmol) in anhydrous THF (10 mL) was added drop wise. The resulting mixture was stirred at -78 °C for an additional 1 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and diluted with EA (30 mLx3). The combined organic layer was washed with saturated Na2S2O3 aqueous solution and brine, dried over anhydrous Na2SO4, fdtered and concentrated under vacuo. The residue was purified by column chromatography on silica gel (PE) to give the desired product (2.79 g, yield: 79%). 1HNMR (400 MHz, DMSO) 6 8.16 (d, J = 3.5 Hz, 1H).

Step 2.2,6-dichloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)-3-fluoropyridine (33-4) 118 WO 2022/002245 PCT/CN2021/104232 id="p-303" id="p-303" id="p-303" id="p-303" id="p-303"

[00303] A mixture of2,6-dichloro-3-fluoro-4-iodopyridine (1.0 g, 3.42 mmol), (1,4- dimethyl-lH-pyrazol-5-yl)boronic acid (0.76 g, 3.43 mmol), PdCl2(dppf) (251 mg, 0.34 mmol) and Na2CO3 (2.0 M in H2O, 3.4 mL) in DME (35 mL) was stirred at °C for 15 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 10:1, V/V) to give the desired product (744 mg, yield: 83%). LC/MS (ESI): m/z 260 [M+H]+.

Step 3. 6-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)-3-fluoro-N-(l-((2- (trimethylsilyl) ethoxy)methyl)-lH-pyrazol-5-yl)pyridin-2-amine (33-6) Pd2(dba)3, Xant-Phos Cs2CO3, dixoane, 100 °C SEM id="p-304" id="p-304" id="p-304" id="p-304" id="p-304"

[00304]A mixture of 2,6-dichloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)-3-fluoropyridine (400 mg, 1.53 mmol), l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-5-amine (3mg, 1.54 mmol), Pd2(dba)3 (141 mg, 0.15 mmol), XantPhos (89 mg, 0.15 mmol) and C82CO3 (1.0 g, 3.06 mmol) in dioxane (25 mL) was stirred at 100 °C for 6 h under Natmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 2:1, V/V) to give the desired product (4mg, yield: 62%). LC/MS (ESI): m/z 437 [M+H]+. 119 WO 2022/002245 PCT/CN2021/104232 Step 4. (R)-4-(l,4-dimethyI-lH-pyrazol-5-yI)-3-fluoro-6-(3-methylmorpholino)-N- (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)pyridin-2-amine (33-8) Pd2(dba)3, Ru-Phos Cs2CO3, dixoane, 100 °C id="p-305" id="p-305" id="p-305" id="p-305" id="p-305"

[00305]A mixture of 6-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)-3-fluoro-N-(l-{[2- (trimethyl silyl)ethoxy]methyl}-lH-pyrazol-5-yl)pyridin-2-amine (400 mg, 0.mmol), (3 R)-3-methylmorpholine (278 mg, 2.74 mmol), Pd2(dba)3 (168 mg, 0.mmol), RuPhos (171 mg, 0.36 mmol) and C82CO3 (1.19 g, 3.65 mmol) in dioxane (mL) was stirred at 100 °C for 6 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 2:1, V/V) to give the desired product (437 mg, yield: 95%). LC/MS (ESI): m/z 502 [M+H]+ Step 5. (R)-4-(l,4-dimethyl-lH-pyrazol-5-yl)-3-fluoro-6-(3-methylmorpholino)-N- (lH-pyrazol-5-yl)pyridin-2-amine (33) TBAF/THF id="p-306" id="p-306" id="p-306" id="p-306" id="p-306"

[00306]A mixture of 4-(l,4-dimethyl-lH-pyrazol-5-yl)-3-fluoro-6-[(3R)-3- methylmorpholin-4-yl]-N-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-5- yl)pyridin-2-amine (417 mg, 0.83 mmol) in TBAF solution (1.0 M in THF, 8 mL, mmol) was stirred at 70 °C for 5 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water (mL><2) and brine, dried over anhydrous Na2SO4, filtered and concentrated. The 120 WO 2022/002245 PCT/CN2021/104232 residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to obtain a brown solid (252 mg), which was further purified by Prep-HPLC (C18, 10- 95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (66.9 mg, yield: 21%). LC/MS (ESI): m/z 372 [M+H]+. 1H NMR (400 MHz, DMSO) 5 12.18 (s, 1H), 8.89 (s, 1H), 7.59 (s, 1H), 131 (s, 1H), 6.51 (s, 1H), 5.94 (s, 1H), 4.20 (d, J = 4.Hz, 1H), 3.97-3.89 (m, 1H), 3.77-3.69 (m, 5H), 3.63 (dd, J= 11.2, 2.7 Hz, 1H), 3.51 (s, 1H), 3.05 (td, J= 12.6, 3.7 Hz, 1H), 1.96 (s, 3H), 1.13 (d, J = 6.6 Hz, 3H).

Example 28 NaBH4, SOCI2, DMF DCMCH3SO2Na 34-4 34-5 34-9 HCI/dioxane Step 1.2,6-dichloro-3-fluoroisonicotinaldehyde (34-3) id="p-307" id="p-307" id="p-307" id="p-307" id="p-307"

[00307]To a solution of 2,6-dichloro-3-fluoropyridine (3 g, 18.07 mmol) in THE (mL) at -78 °C was added EDA (2.5 M in THE, 9.4 mL, 23.50 mmol) drop wise. The mixture was stirred at -78 °C for 1 h, then a solution of ethyl formate (2.2 mL, 27. 121 WO 2022/002245 PCT/CN2021/104232 mmol) in THE (2 mL) was added drop wise. The mixture was stirred at -78 °C for an additional Ih. LC-MS showed the reaction was complete. The mixture was quenched with saturated NH4C1 aqueous solution and extracted with EA (50mLx3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA= 10:1, V/V) to give the desired product (1.7 g, yield: 48 %). 1H NMR (400 MHz, DMSO) 6 10.11 (s, IH), 7.91 (d,J=4.0Hz, IH).

Step 2. (2,6-dichloro-3-fluoropyridin-4-yl)methanol (34-4) id="p-308" id="p-308" id="p-308" id="p-308" id="p-308"

[00308]To a solution of 2,6-dichloro-3-fluoroisonicotinaldehyde (1.7 g, 8.76 mmol) in THF (30 mL) at 0 °C was added NaBH4 (590 mg, 17.53 mmol) portion wise.After the addition, the mixture was stirred at 0 °C for Ih. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (40 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 5:1, V/V) to give the desired product (1.62 g, yield: 95%). LC/MS (ESI): m/z 1[M+H]+.

Step 3. 2,6-dichloro-4-(chloromethyl)-3-fluoropyridine (34-5) id="p-309" id="p-309" id="p-309" id="p-309" id="p-309"

[00309]To a solution of (2,6-dichloro-3-fluoropyridin-4-yl)methanol (1.6 g, 8.16mmol) and DMF (0.05 mL, 0.68 mmol) in DCM (30 mL) at 0 °C was added SOC(1.2 mL, 16.33 mmol) drop wise. The mixture was stirred at room temperature for 122 WO 2022/002245 PCT/CN2021/104232 16h. LC-MS showed the reaction was complete. The reaction mixture was concentrated to give the desired product (1.7 g, yield: 97%). LC/MS (ESI) m/z: 2[M+H]+.

Step 4. 2,6-dichloro-3-fluoro-4-((methylsulfonyl)methyl)pyridine (34-6) id="p-310" id="p-310" id="p-310" id="p-310" id="p-310"

[00310]To a solution of 2,6-dichloro-4-(chloromethyl)-3-fluoropyridine (1.7 g, 7.mmol) in DMF (30 mL) at 0 °C was added CH3SO2Na (1.21 g, 11.89 mmol) portion wise. The mixture was stirred at room temperature for 4 h. LC-MS showed the reaction was complete. The reaction mixture was poured into H2O (20 mL) and extracted with EA (30mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (PE:EA= 3:1, V/V) to give the desired product (1.76 g, yield: 86%). LC/MS (ESI): m/z 258 [M+H]+.

Step 5. 2,6-dichloro-3-fluoro-4-(l-(methylsulfonyl)cyclopropyl)pyridine (34-7) M NaOH, TBAB Toluene Cl id="p-311" id="p-311" id="p-311" id="p-311" id="p-311"

[00311]To a solution of 2,6-dichloro-3-fluoro-4-((methylsulfonyl)methyl)pyridine (1.76 g, 6.82 mmol), 1,2-dibromoethane (1.5 mL, 17.05 mmol) and TBAB (440 mg, 1.36 mmol) in Toluene (60 mL) was added NaOH (10 M in HO, 6.82 mL, 68.mmol). The mixture was stirred at 60 °C for 3 h. LC-MS showed the reaction was complete. The reaction mixture was poured into H2O (30 mL) and extracted with EA (30 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column 123 WO 2022/002245 PCT/CN2021/104232 chromatography on silica gel (PE : EA = 2:1, V/V) to give the desired product (1.6 g, yield: 83%). LC/MS (ESI): m/z 284 [M+H]+.

Step 6. 6-chloro-3-fluoro-4-(l-(methylsulfonyl)cyclopropyl)-N-(l-((2- (trimethylsilyl) ethoxy)methyl)-lH-pyrazol-5-yl)pyridin-2-amine (34-9) id="p-312" id="p-312" id="p-312" id="p-312" id="p-312"

[00312]To a solution of 2,6-dichloro-3-fluoro-4-(l- (methylsulfonyl)cyclopropyl)pyridine (600 mg, 2.11 mmol), l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-amine (450 mg, 2.11 mmol), XantPhos (244 mg, 0.42 mmol) in dioxane (15 mL) were added Pd2(dba)3 (193 mg, 0.21 mmol) and Cs2CO3 (1.38 g, 4.22 mmol). The mixture was stirred at 100 °C for 6 h under Natmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 1:1, V/V) to give the desired product (7mg, yield: 73.5%). LC/MS (ESI): m/z 461 [M+H]+.

Step 1. (R)-3-fluoro-6-(3-methylmorpholino)-4-(l-(methylsulfonyl)cyclopropyl)- N-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)pyridin-2-amine (34-11) id="p-313" id="p-313" id="p-313" id="p-313" id="p-313"

[00313]To a solution of 6-chloro-3-fluoro-4-(l-(methylsulfonyl)cyclopropyl)-N-(l- ((2-(tri methylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)pyridin-2-amine (640 mg, 1.mmol), (3 R)-3-methylmorpholine (281 mg, 2.78 mmol) andRuPhos (130 mg, 0.124 WO 2022/002245 PCT/CN2021/104232 mmol) in dioxane (15 mL) were added Pd2(dba)3 (127 mg, 0.14 mmol) and Cs2CO(1.36 g, 4.16 mmol). The mixture was stirred at 100 °C for 16 h under Natmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (DCM : MeOH = 50:1, V/V) to give the desired product (450 mg, yield: 62%). LC/MS (ESI): m/z 527 [M+H]+.

Step 8. (R)-3-fluoro-6-(3-methylmorpholino)-4-(l-(methylsulfonyl)cyclopropyl)- N-(lH-pyrazol-5-yl)pyridin-2-amine (34) id="p-314" id="p-314" id="p-314" id="p-314" id="p-314"

[00314]A mixture of (R)-3-fluoro-6-(3-methylmorpholino)-4-(l- (methylsulfonyl)cyclo propyl)-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5- yl)pyridin-2-amine (450 mg, 0.86 mmol) in HC1 solution (4M in dioxane, 5 mL) was stirred at 60 °C for 1.5 h. LC-MS showed the reaction was complete. The mixture was concentrated under vacuo. The residue was purified by flash column chromatography on silica gel (DCM : MeOH = 30:1, V/V) to afford a pale-yellow oil, which was further purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (45 mg, yield: 13%). LC/MS (ESI): m/z 3[M+H]+. 1H NMR (400 MHz, DMSO) 5 12.17 (s, 1H), 8.80 (s, 1H), 7.58 (s, 1H), 6.47 (s, 1H), 6.11 (s, 1H), 4.22-4.15 (m, 1H), 3.93 (dd, J= 11.2, 3.1 Hz, 1H), 3.74- 3.66 (m, 2H), 3.61 (dd, J = 11.3, 2.7 Hz, 1H), 3.48-3.46 (m, 1H), 3.04 (dd, J = 12.5, 3.7 Hz, 1H), 2.98 (s, 3H), 1.70- 1.62 (m, 2H), 1.37- 1.30 (m, 2H), 1.11 (d, 1 = 6.Hz, 3H).

Example 29 125 WO 2022/002245 PCT/CN2021/104232 1-5 1,2-dibromoethane, KOH, TBAB, 2-Me-THF, H20 BrettPhos-Pd-G3, Cs2CO3dioxane, 100°C Step 1. 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}acetonitrile (35- 1) NaCNDMSO id="p-315" id="p-315" id="p-315" id="p-315" id="p-315"

[00315]To a solution of (3R)-4-[6-chloro-4-(chloromethyl)pyridin-2-yl]-3- methylmorpholine (778 mg, 2.98 mmol) in DMSO (15 mL) was added NaCN (2mg, 4.47 mmol) portion wise. The mixture was stirred at ambient temperature overnight. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA= 3:1, V/V) to give the desired product (253 mg, yield: 34%). LC/MS ESI (m/z): 252 [M+H]+.

Step 2. l-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclopropane-l- carbonitrile (35-2) 126 WO 2022/002245 PCT/CN2021/104232 1,2-dibromoethane, KOH، TBAB, 2-Me-THF, H2O id="p-316" id="p-316" id="p-316" id="p-316" id="p-316"

[00316]A mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl} acetonitrile (80 mg, 0.32 mmol), 1,2-dibromoethane (0.06 mL, 0.64 mmol), KOH (500 mg, 8.91 mmol) and TBAB (21 mg, 0.06 mmol) in 2-Methyltetrahydrofuran (mL) and H2O (0.5 mL) was stirred at 60 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =2:1, V/V) to give the desired product (64 mg, yield: 73%). LC/MS ESI (m/z): 278 [M+H]+.

Step 3. tert-butyl 5-{[4-(l-cyanocyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl] pyridin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate (35-3) BrettPhos-Pd-G 3, Cs2COdioxane, 100°C id="p-317" id="p-317" id="p-317" id="p-317" id="p-317"

[00317]A mixture of l-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl}cyclo propane-l-carbonitrile (64 mg, 0.23 mmol), tert-butyl 5-amino-3-methyl-lH- pyrazole-1-carboxylate (68 mg, 0.35 mmol), BrettPhos-Pd-G3 (20 mg, 0.02 mmol) and C82CO3 (225 mg, 0.69 mmol) in dioxane (6 mL) was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to give the desired product (62 mg, yield: 61%). LC/MS ESI (m/z): 439 [M+H]+. 127 WO 2022/002245 PCT/CN2021/104232 Step 4. l-{2-[(3-methyl-lH-pyrazol-5-yl)amino]-6-[(3R)-3-methylmorpholin-4- yl]pyridin-4-yl}cyclopropane-l-carbonitrile (35) id="p-318" id="p-318" id="p-318" id="p-318" id="p-318"

[00318]A solution of tert-butyl 5-{[4-(l-cyanocyclopropyl)-6-[(3R)-3- methylmorpholin-4-yl] pyridin-2-yl]amino}-3-methyl-lH-pyrazole-l-carboxylate (mg, 0.14 mmol) in HC1 solution (4 M in dioxane, 4 mL) was stirred at ambient temperature overnight. LC-MS showed the reaction was complete The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (15.4 mg, yield: 32%). LC/MS ESI (m/z): 339 [M+H]+ 1HNMR (400 MHz, DMSO) 11.72 (br, 1H), 8.81 (s, 1H), 6.57 (s, 1H), 5.99 (s, 1H), 5.77 (s, 1H), 4.30 (d, J = 6.Hz, 1H), 3.92 (dd, J - 11.2, 3.2 Hz, 1H), 3.76 (d, J - 12.7 Hz, 1H), 3.71 (d, J11.Hz, 1H), 3.60 (dd, J= 11.2, 2.8 Hz, 1H), 3.47-3.44 (m, 1H), 3.03 (dd, J= 12.6, 9.Hz, 1H), 2.17 (s, 3H), 1.71 (dd, J = 7.5, 4.4 Hz, 2H), 1.50 (dd, J = 7.7, 4.4 Hz, 2H), 1.11 (d, J-6.6 Hz, 3H). 36-1 Example 30 Brettphos-Pd-G3 Step 1. (R)-N-(3-methyl-lH-pyrazol-5-yl)-6-(3-methylmorpholino)-4-(4-(methyl sulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-amine (36) 128 WO 2022/002245 PCT/CN2021/104232 Brettphos-Pd-G3 id="p-319" id="p-319" id="p-319" id="p-319" id="p-319"

[00319]To a solution of (R)-4-(6-chloro-4-(4-(methylsulfonyl)tetrahydro-2H-pyran- 4־yl) pyridin-2-yl)-3-methylmorpholine (100 mg, 0.27 mmol), tert-butyl 5-amino-3- methyl-lH-pyrazole-l-carboxylate (105 mg, 0.53 mmol) and Cs2CO3 (261 mg, 0.mmol) in dioxane (8 mL) was added BrettPhos-Pd-G3 (24 mg, 0.027 mmol). The mixture was stirred at 100 °C for 16 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (12 mg, yield: 10 %). LC/MS (ESI): m/z 436 [M+H]+. LHNMR(400 MHz, DMSO) 8 11.69 (s, 1H), 8.82 (s, 1H), 6.70 (s, 1H), 6.17 (s, 1H), 6.05 (s, 1H), 4.31 - 4.23 (m, 1H), 3.96 - 3.83 (m, 4H), 3.72 (d, J = 11.2 Hz, 1H), 3.64 (dd, J= 11.2, 2.7 Hz, 1H), 3.49 (td, J = 11.7, 2.8 Hz, 1H), 3.26- 3.18 (m, 2H), 3.05 (td, J = 12.7, 3.6 Hz, 1H), 2.71 (s, 3H), 2.43 (d, J = 13.7 Hz, 2H), 2.24 -2.16 (m, 5H), 1.12 (d, J - 6.6 Hz, 3H).

Example 31 Step 1. 1- {2-chloro-6- [(3R)-3-methylmor pholin-4-yl] pyridin-4-yl}cyclopentane-1- carbonitrile (37-1) 129 WO 2022/002245 PCT/CN2021/104232 1,4-dibromobutane,TBAB,2-Me-THF,H20" id="p-320" id="p-320" id="p-320" id="p-320" id="p-320"

[00320]A mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl}acetonitrile (210 mg, 0.83 mmol), 1,4-dibromobutane (1 mL, 8.34 mmol), KOH (g, 53.47 mmol) and TBAB (54 mg, 0.17 mmol) in co-solvent of 2- methyltetrahydrofuran (15 mL) and H2O (3 mL) was stirred at 70 °C overnight. LC- MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA= 3:1, V/V) to give the desired product (192 mg, yield: 75%). LC/MS ESI (m/z): 306 [M+H]+.

Step 2. tert-butyl 5-{[4-(l-cyanocyclopentyl)-6-[(3R)-3-methylmorpholin-4-yl] pyridin-2-yl]amino}-lH-pyrazole-l-carboxylate (37-2) BrettPhos-Pd-G 3, Cs2COdioxane, 100°C id="p-321" id="p-321" id="p-321" id="p-321" id="p-321"

[00321]To a solution of l-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl}cyclo pentane-1-carbonitrile (100 mg, 0.33 mmol) and tert-butyl 5-amino-lH- pyrazole-1-carboxylate (90 mg, 0.49 mmol) in dioxane (10 mL) were added BrettPhos-Pd-G3 (29.6 mg, 0.03 mmol) and C82CO3 (319.6 mg, 0.98 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to give the desired product (104 mg, yield: 70%). LC/MS ESI (m/z): 453 [M+H]+.130 WO 2022/002245 PCT/CN2021/104232 Step 3. l-{2-[(3R)-3-methylmorpholin-4-yl]-6-[(lH-pyrazol-5-yl)amino]pyridin-4- yl} cyclopentane- 1-carbonitrile (37) id="p-322" id="p-322" id="p-322" id="p-322" id="p-322"

[00322]A mixture of tert-butyl 5-{[4-(l-cyanocyclopentyl)-6-[(3R)-3- methylmorpholin-4-yl]pyridin-2-yl]amino}-lH-pyrazole-l-carboxylate (104 mg, 0.mmol ) in HC1 solution (4 M in dioxane, 4 mL) was stirred at ambient temperature overnight. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (C18, 10- 95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (42.5 mg, yield: 52%). LC/MS ESI (m/z): 353 [M+H]+. 1HNMR (400 MHz, DMSO) 3 12.14 (s, 1H), 9.01 (s, 1H), 7.54 (d, J = 2.2 Hz, 1H), 6.59 (s, 1H), 6.30 (d, J = 2.2 Hz, 1H), 6.07 (d, J = 0.9 Hz, 1H), 4.35-4.29 (m, 1H), 3.93 (dd,J= 11.2, 3.3 Hz, 1H), 3.79 (d, J = 13.Hz, 1H), 3.73 (d, J= 11.2 Hz, 1H), 3.62 (dd, J = 11.3, 2.8 Hz, 1H), 3.48 (dd, J = 11.8, 2.9 Hz, 1H), 3.09 - 3.02 (m, 1H), 2.34 - 2.28 (m, 2H), 2.10 - 2.03 (m, 2H), 1.90 - 1.85 (m, 4H), 1.13 (d, J = 6.6 Hz, 3H) Example 32 Step 1. l-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclohexane-l- carbonitrile (38-1) 131 WO 2022/002245 PCT/CN2021/104232 1,5-dibromopentane, KOHTBAB, 2-Me-THF, H2O id="p-323" id="p-323" id="p-323" id="p-323" id="p-323"

[00323]A mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl} acetonitrile (210 mg, 0 83 mmol), 1,5-dibromopentane (1.2 mL, 8 34 mmol), KOH (3 g, 53.47 mmol) and TBAB (54 mg, 0.17 mmol) in co-solvent of 2- methyltetrahydrofuran (15 mL) and H2O (3 mL) was stirred at 70 °C overnight. LC- MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA= 3:1, V/V) to give the desired product (194 mg, yield: 73%). LC/MS ESI (m/z): 320 [M+H]+.

Step 2. tert-butyl 5-{[4-(l-cyanocyclohexyl)-6-[(3R)-3-methylmorpholin-4-yl] pyridin-2-yl]amino}-lH-pyrazole-l-carboxylate (38-2) id="p-324" id="p-324" id="p-324" id="p-324" id="p-324"

[00324]To a solution of l-[2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl}cyclohexane-l-carbonitrile (100 mg, 0.31 mmol) and tert-butyl 5-amino-lH- pyrazole-1-carboxylate (86 mg, 0.47 mmol) in dioxane (10 mL) were added BrettPhos-Pd-G3 (28 mg, 0.03 mmol) and Cs2CO3 (306 mg, 0.94 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue 132 WO 2022/002245 PCT/CN2021/104232 was purified by column chromatography on silica gel (PE : EA =1:1, V/V) to give the desired product (102 mg, yield: 70%). LC/MS ESI (m/z): 467 [M+H]+.

Step 3. l-{2-[(3R)-3-methylmorpholin-4-yl]-6-[(lH-pyrazol-5-yl)amino]pyridin-4- yl} cyclohexane-l-carbonitrile (38) id="p-325" id="p-325" id="p-325" id="p-325" id="p-325"

[00325]A mixture of tert-butyl 5-{[4-(l-cyanocyclohexyl)-6-[(3R)-3- methylmorpholin-4-yl] pyridin-2-yl]amino}-lH-pyrazole-l-carboxylate (102 mg, 0.22 mmol) in HC1 solution (4 M in dioxane, 4 mL) was stirred at ambient temperature overnight. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (36.6 mg, yield: 46%). LC/MS ESI (m/z): 367 [M+H]+. 1HNMR (400 MHz, DMSO) 12.17 (s, 1H), 9.00 (s, 1H), 7.53 (d, J = 2.2 Hz, 1H), 6.63 (s, 1H), 6.29 (d, J = 2.Hz, 1H), 6.11 (d, J = 0.8 Hz, 1H), 4.32 (d, J = 6.6 Hz, 1H), 3.93 (dd, J = 11.2, 3.3 Hz, 1H), 3.80 (d, J = 11.3 Hz, 1H), 3.73 (d, J = 11.1 Hz, 1H), 3.62 (dd, J = 11.3, 2.8 Hz, 1H), 3.47 (td, J= 11.8, 3.0 Hz, 1H), 3.05 (td,J = 12.6, 3.7 Hz, 1H), 2.00 (d, J = 12.Hz, 2H), 1.81 (dd, J= 16.4, 6.6 Hz, 4H), 1.73 (d, J = 13.6 Hz, 1H), 1.66- 1.56 (m, 2H), 1.34 - 1.24 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H).

Example 33 133 WO 2022/002245 PCT/CN2021/104232 Step 1. (R)-4-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)tetrahydro-2H- pyran-4-carbonitrile (39-1) id="p-326" id="p-326" id="p-326" id="p-326" id="p-326"

[00326]A mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl}acetonitrile (180 mg, 0.72 mmol), 1-brom o-2-(2-bromoethoxy )ethane (660 mg, 2.85 mmol), TBAB (46 mg, 0.14 mmol) and NaOH (10.0 M in H:O, 14.0 mmol, 1.mL) in toluene (10 mL) was stirred at 60 °C for 2 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated under vacuo. The residue was purified by column chromatography on silica gel (PE : EA = 2:1, V/V) to afford the desired product (157 mg, yield: 68%). LC/MS (ESI): m/z 322 [M+H]+.

Step 2. (R)-4-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl) tetrahydro-2H-pyran-4-carbonitrile (39) id="p-327" id="p-327" id="p-327" id="p-327" id="p-327"

[00327]A mixture of 4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4- yl}oxane-4-carbonitrile (80 mg, 0.25 mmol), lH-pyrazol-5-amine (41 mg, 0.mmol), BrettPhos-Pd-G3 (22 mg, 0.02 mmol) and Cs2CO3 (244 mg, 0.75 mmol) in dioxane (4 mL) was stirred at 110 °C for 16 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (37 mg, yield: 40%). LC/MS (ESI): m/z 369 134 WO 2022/002245 PCT/CN2021/104232 [M+H]+. 1HNMR (400 MHz, DMSO) 5 12.06 (s, 1H), 9.04 (s, 1H), 7.54 (d, J = 1.Hz, 1H), 6.64 (s, 1H), 6.29 (s, 1H), 6.13 (s, 1H), 4.34 (d, J = 6.9 Hz, 1H), 4.00 (dd, J = 11.2, 3.0 Hz, 2H), 3.93 (dd, J = 11.3, 3.3 Hz, 1H), 3.82 (d, J = 12.8 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 3.68 - 3.59 (m, 3H), 3.47 (td, J = 11.8, 2.9 Hz, 1H), 3.06 (td, J = 12.6, 3.7 Hz, 1H), 2.13-1.95 (m, 4H), 1.13 (d, J = 6.6 Hz, 3H).

Example 34 40-1 40 Step 1. (R)-l-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclopentane-l- carbonitrile (40-1) id="p-328" id="p-328" id="p-328" id="p-328" id="p-328"

[00328]To a solution of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4- yl)acetonitrile (200 mg, 0.79 mmol), 1,4-dibromobutane (0.95 mL, 7.91 mmol) and TBAB (26 mg, 0.08 mmol) in 2-MeTHF (15 mL) was added KOH aqueous solution (10 M, 1.58 mL, 15.8 mmol). The mixture was stirred at 70 °C overnight. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 10:1, V/V) to give the desired product (220 mg, yield: 91 %). LC/MS (ESI): m/z 307 [M+H]+.

Step 2. (R)-l-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4- 135 WO 2022/002245 PCT/CN2021/104232 yl) cyclopentane-l-carbonitrile (40) id="p-329" id="p-329" id="p-329" id="p-329" id="p-329"

[00329]To a suspension of (R)-l-(2-chloro-6-(3-methylmorpholino)pyrimidin-4- yl)cyclo pentane-l-carbonitrile (100 mg, 0.33 mmol), lH-pyrazol-5-amine (41 mg, 0.49 mmol) and C82CO3 (319 mg, 0.98 mmol) in dioxane (8 mL) was added BrettPhos-Pd-G3 (29 mg, 0.03 mmol). The mixture was stirred at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (30 mg, yield: 26%). LC/MS (ESI): m/z 354.4 [M+H]+. 1H NMR (400 MHz, DMSO) 8 12.(s, 1H), 9.19 (s, 1H), 7.52 (s, 1H), 6.49 (s, 1H), 6.28 (s, 1H), 4.40 (d, J = 5.4 Hz, 1H), 4.00 (d, J = 12.9 Hz, 1H), 3.93 (dd, J = 11.3, 3.3 Hz, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.59 (dd, 1= 11.4, 2.9 Hz, 1H), 3.46-3.40 (m, 1H), 3.14 (td, J= 12.9, 3.7 Hz, 1H), 2.31-2.22 (m, 4H), 1.89- 1.82 (m, 4H), 1.19 (d, J = 6.7 Hz, 3H).

Example 35 1-5 Step 1. (R)-l-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclohexane-l- carbonitrile (41-1) 136 WO 2022/002245 PCT/CN2021/104232 id="p-330" id="p-330" id="p-330" id="p-330" id="p-330"

[00330]To a suspension of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl) acetonitrile (200 mg, 0.79 mmol), 1,5-dibromopentane (1.08 mL, 7.91 mmol) and TBAB (26 mg, 0.08 mmol) in 2-MeTHF (15 mL) was added KOH aqueous solution (10 M, 1.58 mL, 15.8 mmol). The mixture was stirred at 70 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 10:1, V/V) to give the desired product (210 mg, yield: 83 %). LC/MS (ESI): m/z 321 [M+H]+.

Step 2. (R)-l-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4- yl)cyclohexane-l-carbonitrile (41) id="p-331" id="p-331" id="p-331" id="p-331" id="p-331"

[00331]To a suspension of (R)-l-(2-chloro-6-(3-methylmorpholino)pyrimidin-4- yl)cyclo hexane-1-carbonitrile (100 mg, 0.31 mmol), lH-pyrazol-5-amine (39 mg, 0.47 mmol) and C82CO3 (305 mg, 0.94 mmol) in dioxane (8 mL) was added BrettPhos-Pd-G3 (28 mg, 0.03 mmol). The mixture was stirred at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (20 mg, yield: 17.5%). LC/MS (ESI): m/z 368.5 [M+H]+. 1H NMR (400 MHz, DMSO) 8 12.09 (s, 1H), 9.137 WO 2022/002245 PCT/CN2021/104232 (s, 1H), 7.51 (s, 1H), 6.52 (s, 1H), 6.26 (s, 1H), 4.46- 4.34 (m, 1H), 4.01 (d, J= 13.Hz, 1H), 3.93 (dd, J= 11.4, 3.3 Hz, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.58 (dd, J= 11.4, 3.0 Hz, 1H), 3.43 (td, J = 11.9, 2.9 Hz, 1H), 3.14 (td, J = 12.8, 3.6 Hz, 1H), 2.09 - 2.02 (m, 2H), 1.95 - 1.86 (m, 2H), 1.85 - 1.78 (m, 2H), 1.77 - 1.70 (m, 1H), 1.65 - 1.53 (m, 2H), 1.32 - 1.22 (m, 1H), 1.19 (d, J = 6.7 Hz, 3H).

Example 36 Brettphos Pd G3 Step 1. (R)-4-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carbonitrile (42-1) id="p-332" id="p-332" id="p-332" id="p-332" id="p-332"

[00332]To a solution of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4- yl)acetonitrile (200 mg, 0.79 mmol) in Toluene (10 mL) were added l-bromo-2-(2- bromo ethoxy)ethane (367 mg, 1.58 mmol), Sodium hydroxide (10 M in H2O, 0.mL, 7.91 mmol) and TBAB (52 mg, 0.16 mmol). The reaction was stirred at 60 °C overnight. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE : EA= 3:1, V/V) to afford the desired product (180 mg, yield: 70%). LC/MS (ESI): m/z 323 [M+H]+.

Step 2. (R)-4-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4- 138 WO 2022/002245 PCT/CN2021/104232 yl) tetrahydro-2H-pyran-4-carbonitrile (42) id="p-333" id="p-333" id="p-333" id="p-333" id="p-333"

[00333]To a solution of (R)-4-(2-chloro-6-(3-methylmorpholino)pyrimidin-4- yl)tetrahydro -2H-pyran-4-carbonitrile (80 mg, 0.25 mmol) in dioxane (8 mL) were added lH-pyrazol-5-amine (31 mg, 0.37 mmol), C82CO3 (162 mg, 0.50 mmol) and BrettPhos-Pd-G3 (45 mg, 0.05 mmol). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep - HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to afford the desired product (15 mg, yield: 16%). LC/MS (ESI): m/z 370 [M+H]+. HNMR (400 MHz, DMSO)8 12.10 (s, 1H), 9.14 (s, 1H), 7.54 (s, 1H), 6.60 (s, 1H), 6.29 (s, 1H), 4.43 (s, 1H), 4.07 - 3.96 (m, 3H), 3.93 (dd, J = 11.4, 3.4 Hz, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.63 (dd, J = 12.0, 10.3Hz, 2H), 3.57 (d, J = 3.0 Hz, 1H), 3.43 (td, J = 11.9, 2.9 Hz, 1H), 3.15 (td, J = 12.9, 3.6 Hz, 1H), 2.20 - 2.12 (m, 2H), 2.03 (d, J = 12.3 Hz, 2H), 1.20 (d, J = 6.7 Hz, 3H).

Example 37 Step 1. l-(2,6-dichloropyridin-4-yl)cyclohexan-l-ol (43-3) 139 WO 2022/002245 PCT/CN2021/104232 Cl BuLi, THF id="p-334" id="p-334" id="p-334" id="p-334" id="p-334"

[00334]To a solution of 4-bromo-2,6-dichloropyridine (300 mg, 1.32 mmol) and cyclo- hexanone (156 mg, 1.59 mmol) in THF (8 mL) at -78 °C was added n-BuLi solution (2.5 M in THF, 0.74 mL, 1.85 mmol) drop wise. The mixture was stirred at - °C for 1 h. LC-MS showed the reaction was complete. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (3 0mL* 3) thrice. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA= 10:1, V/V) to give the desired product (2mg, yield: 77%). LC/MS (ESI): m/z 246 [M+H]+.

Step 2. (R)-l-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)cyclohexan-l-ol (43-5) id="p-335" id="p-335" id="p-335" id="p-335" id="p-335"

[00335]To a solution of l-(2,6-dichloropyridin-4-yl)cyclohexan-l-ol (250 mg, 1.mmol) in NMP (5 mL) was added (3R)-3-methylmorpholine (308 mg, 3.05 mmol). The mixture was stirred at 150 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA= 5:1, V/V) to give the desired product (42 mg, yield: 13.3 %). LC/MS (ESI): m/z 311 [M+H]+.

Step 3. (R)-l-(2-((lH-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl) cyclohexan-l-ol (43) 140 WO 2022/002245 PCT/CN2021/104232 id="p-336" id="p-336" id="p-336" id="p-336" id="p-336"

[00336]To a suspension of (R)-l-(2-chloro-6-(3-methylmorpholino)pyridin-4- yl)cyclohexan-l-ol (42 mg, 0.135 mmol), lH-pyrazol-5-amine (23 mg, 0.270 mmol) and C82CO3 (132 mg, 0.405 mmol) in dioxane (6 mL) was added BrettPhos-Pd-G(12 mg, 0.01 mmol). The mixture was stirred at 100 °C for 16 h under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (10 mg, yield: 21%). LC/MS (ESI): m/z 358 [M+H]+. LHNMR(400 MHz, DMSO) 8 12.17 (s, 1H), 8.74 (s, 1H), 7.50 (d, J = 2.2 Hz, 1H), 6.54 (s, 1H), 6.28 (d, J = 2.0 Hz, 1H), 6.15 (s, 1H), 4.(s, 1H), 4.32-4.23 (m, 1H), 3.93 (dd, J= 11.1, 3.1 Hz, 1H), 3.77-3.68 (m, 2H), 3.(dd, J = 11.2, 2.8 Hz, 1H), 3.47 (td, J = 11.7, 2.9 Hz, 1H), 3.03 (td, J = 12.5, 3.6 Hz, 1H), 1.73 - 1.53 (m, 7H), 1.51-1.43 (m, 2H), 1.27-1.17 (m, 1H), 1.11 (d, J = 6.Hz, 3H).

Example 38 141 WO 2022/002245 PCT/CN2021/104232 Step 1. 4-bromo-2,6-dichloropyrimidine (44-3) Cl LiTMP, THF id="p-337" id="p-337" id="p-337" id="p-337" id="p-337"

[00337]To a solution of 2,4-dichloropyrimidine (1 g, 6.71mmol) in THF (50 mL) at - °C was added Lithium tetramethylpiperidide solution (1.0 M in THF, 8.0 mL, 8.mmol) dropwise. The mixture was stirred at -60 °C for 1 h, then a solution of 1,2- dibromo-1,1,2,2-tetrachloroethane (3.28 g, 10.07 mmol) in THF (5 mL) was added dropwise. The resulting mixture was stirred at -60 °C for an additional 2 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (60 mL). The organic layer was separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE : EA= 50:1, V/V) to afford the desired product (600 mg, yield: 39%). LC/MS (ESI): m/z 228 [M+H]+.

Step 2. l-(2,6-dichloropyrimidin-4-yl)cyclohexan-l-ol (44-5) id="p-338" id="p-338" id="p-338" id="p-338" id="p-338"

[00338]To a solution of 4-bromo-2,6-dichloropyrimidine (600 mg, 2.63 mmol) and cyclohexanone (0.32 mL, 3.16 mmol) in THF (15 mL) at -60 °C was added n- Butyllithium (2.5 M in THF, 1.5 mL, 3.69 mmol) dropwise. The mixture was stirred at -60 °C for 30 min. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (60 mL). The organic layer was separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography 142 WO 2022/002245 PCT/CN2021/104232 on silica gel (PE : EA = 20:1, V/V) to afford the desired product (200 mg, yield: 30%). LC/MS (ESI): m/z 248 [M+H]+.

Step 3. (R)-l-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclohexan-l-ol (44-7) id="p-339" id="p-339" id="p-339" id="p-339" id="p-339"

[00339]To a solution of l-(2,6-dichloropyrimidin-4-yl)cyclohexan-l-ol (200 mg, 0.81 mmol) in NMP (5 mL) was added (R)-3-methylmorpholine (246 mg, 2.mmol). The mixture was stirred at 120 °C for 1 h under microwave irradiation. EC- MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE : EA= 10:1, V/V) to afford the desired product (200 mg, yield: 79%). LC/MS (ESI): m/z 312 [M+H]+.

Step 4. (R)-l-(2-((lH-pyrazol-5-yl)amino)-6-(2-methylpiperidin-l-yl)pyrimidin-4- yl) cyclohexan-l-ol (44) id="p-340" id="p-340" id="p-340" id="p-340" id="p-340"

[00340]To a solution of (R)-l-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclohexan-l-ol (80 mg, 0.26 mmol) in Dioxane (2 mL) were added lH-pyrazol-5- amine (32 mg, 0.39 mmol), C82CO3 (167 mg, 0.51 mmol) and BrettPhos-Pd-G3 (mg, 0.03 mmol). The mixture was stirred at 80 °C overnight under nitrogen143 WO 2022/002245 PCT/CN2021/104232 atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep -HPLC (Cl 8, 10-95%, MeOH in H2O with 0.1% HCOOH) to afford the desired product (20 mg, yield: 21%). LC/MS (ESI) m/z: 317 [M+H]+. 1HNMR(400 MHz, DMSO) 5 8.99 (s, 1H), 7.50 (d, J= 2.Hz, 1H), 6.41 (d, J= 1.7 Hz, 1H), 6.38 (s, 1H), 4.86 (s, 1H), 4.35 (d, J= 4.7 Hz, 1H), 3.94 (dd, J= 19.7, 8.5 Hz, 2H), 3.73 (d, J= 11.3 Hz, 1H), 3.58 (d, J= 8.5 Hz, 1H), 3.43 (d,J=2.9Hz, 1H), 3.12 (dd, J= 12.6, 9.2 Hz, 1H), 1.85 (dt, J= 12.2, 7.2 Hz, 2H), 1.69 (dd, J=24.2, 11.5 Hz, 3H), 1.49 (t,J= 13.8 Hz, 4H), 1.24 (s, 1H), 1.18 (d, J=6.7Hz, 3H).

Example 39 1-5 45-1 Brettphos-Pd-G3 Step 1. (R)-4-(6-chloro-4-((methylsulfonyl)methyl)pyridin-2-yl)-3- methylmorpholine (45-1) CH3SO2Na DMF id="p-341" id="p-341" id="p-341" id="p-341" id="p-341"

[00341]To a solution of (3R)-4-[6-chloro-4-(chloromethyl)pyridin-2-yl]-3- methylmorpholine (2 g, 7.66 mmol) in DMF (40 mL) was added CH3SO2Na (1.56 g, 15.32 mmol). The mixture was stirred at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (100 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA= 10:1, V/V) to give the desired product (1.6 g, yield: 68 %). LC/MS (ESI): m/z 305 [M+H]+. 144 WO 2022/002245 PCT/CN2021/104232 Step 2. (R)-4-(6-chloro-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2- yl)-3-methylmorpholine (45-2) id="p-342" id="p-342" id="p-342" id="p-342" id="p-342"

[00342]To a solution of (R)-4-(6-chloro-4-((methylsulfonyl)methyl)pyridin-2-yl)-3- methylmorpholine (800 mg, 2.62 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.83 g, 7.87 mmol) and TBAB (170 mg, 0.53 mmol) in Toluene (26 mL) was added NaOH aqueous solution (10 M, 2.63 mL, 26.25 mmol). The mixture was stirred at 60 °C for h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA= 10:1, V/V) to give the desired product (5mg, yield: 56 %). LC/MS (ESI): m/z 375 [M+H]+.

Step 3. (R)-6-(3-methylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran- 4-yl)-N-(lH-pyrazol-5-yl)pyridin-2-amine (45) id="p-343" id="p-343" id="p-343" id="p-343" id="p-343"

[00343]To a solution of (R)-4-(6-chloro-4-(4-(methylsulfonyl)tetrahydro-2H-pyran- 4־yl) pyridin-2-yl)-3-methylmorpholine (100 mg, 0.27 mmol), lH-pyrazol-5-amine (44 mg, 0.53 mmol) and C82CO3 (261 mg, 0.80 mmol) in dioxane (8 mL) was added BrettPhos -Pd-G3 (24 mg, 0.03 mmol). The mixture was stirred at 100 °C for 5 h. LC- 145 WO 2022/002245 PCT/CN2021/104232 MS showed the reaction was complete. The reaction mixture was diluted with EA (mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1% HCOOH) to give the desired product (37 mg, yield: 33 %). LC/MS (ESI): m/z 422 [M+H]+. LHNMR(400 MHz, DMSO) 5 11.94 (s, 1H), 8.98 (s, 1H), 7.54 (d, J = 2.2 Hz, 1H), 6.61 (s, 1H), 6.35 (d, J = 2.1 Hz, 1H), 6.18 (s, 1H), 4.- 4.23 (m, 1H), 3.97 -3.83 (m, 4H), 3.73 (d, J = 11.1 Hz, 1H), 3.64 (dd, J = 11.2, 2.Hz, 1H), 3.52 - 3.46 (m, 1H), 3.26 - 3.20 (m, 2H), 3.06 (td, J - 12.7, 3.7 Hz, 1H), 2.71 (s, 3H), 2.44 (d, J = 13.7 Hz, 2H), 2.25 - 2.14 (m, 2H), 1.12 (d, J = 6.6 Hz, 3H).

Example 40 Pd(dppf)CI2, K2CO3, dioxaneCs2CO3, dioxane, BrettPhos Pd G3 Step 1: (R)-4-(6-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)pyridin-2-yl)-3- methylmorpholine (46-2) id="p-344" id="p-344" id="p-344" id="p-344" id="p-344"

[00344]To a solution of (R)-4-(6-chloro-4-iodopyridin-2-yl)-3-methylmorpholine (150 mg, 0.44 mmol) and l,4-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole (108.24 mg, 0.49 mmol) in dioxane (5 mL) were added K2CO(121.44 mg, 0 89 mmol) and Pd(dppf)C12 (32.20 mg, 0.04 mmol). The mixture was charged with N2 twice, then stirred at 90 °C for 12 hrs. The reaction mixture was diluted with water (10 mL) and extracted with EA (15 mL * 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting mixture was purified by flash chromatography 146 WO 2022/002245 PCT/CN2021/104232 eluting with PE/EtOAc (3:1, V/V) to afford the desired product (110 mg, yield: 80.93%).

Step 2: tert-butyl (R)-5-((4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-(3- methylmorpholino)pyridin-2-yl)amino)-3-methyl-lH-pyrazole-l-carboxylate (46- 3) id="p-345" id="p-345" id="p-345" id="p-345" id="p-345"

[00345]To a solution of (R)-4-(6-chloro-4-(l,4-dimethyl-lH-pyrazol-5-yl)pyridin-2- yl)-3-methylmorpholine (110 mg, 0.36 mmol) and tert-butyl 5-amino-3-methyl-lH- pyrazole-1-carboxylate (84.86 mg, 0.43 mmol) in dioxane (5 mL) were added CS2CO3 (350.47 mg, 1.08 mmol) and BrettPhos Pd G3 (32.67 mg, 0.036 mmol). The mixture was charged with N2 twice, then stirred at 90 °C overnight. The reaction was diluted with water and extracted with EtOAc (10 mLx2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting mixture was purified by flash chromatography eluting with PE/EtOAc (2:1, V/V) to afford the desired product (120 mg, yield: 71.58%).

Step 3: (R)-4-(l,4-dimethyl-lH-pyrazol-5-yl)-N-(3-methyl-lH-pyrazol-5-yl)-6-(3- methylmorpholino)pyridin-2-amine (46) 147 WO 2022/002245 PCT/CN2021/104232 id="p-346" id="p-346" id="p-346" id="p-346" id="p-346"

[00346]A mixture of tert-butyl (R)-5-((4-(l,4-dimethyl-lH-pyrazol-5-yl)-6-(3-methyl morpholino)pyridin-2-yl)amino)-lH-pyrazole-l-carboxylate (50 mg, 0.11 mmol) in DCM (3 mL) was added TFA (1 mL), the mixture was stirred at room temperature for h. The resulting mixture was concentrated in vacuo. The saturated solution of NaHCO3 was added to the mixture until pH=7~8, and extracted with DCM (mLx2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Pre-TLC (DCM/MeOH=10/l, V/V) to afford the desired product (10 mg, yield 25.45 %). LC/MS (ESI) m/z: 368.1 [M+H]+. 1HNMR (400 MHz, DMSO-t/6) 5 ppm 11.69 (br s, 1 H) 8.88 (br s, 1 H) 7.31 (s, 1 H) 6.49 (br s, 1 H) 6.05 (br s, 1 H) 5.98 - 6.01 (m, 1 H) 4.29 (brd,.J=6.16Hz, 1 H) 3.86 - 3.96 (m, 2 H) 3.73 (s, 3 H)3.69- 3.72 (m, 1 H) 3.61 - 3.66 (m, 1 H) 3.45 - 3.52 (m, 1 H) 3.07 (td, >12.58, 3.34 Hz, H) 2.18 (s, 3 H) 1.98 (s, 3 H) 1.15 (d, >6.54 Hz, 3 H).

Example 41 Step 1. (R)-4-(3,5-dimethylisoxazol-4-yl)-N-(3-methyl-lH-pyrazol-5-yl)-6-(3- methylmorpholino)pyridin-2-amine (47) id="p-347" id="p-347" id="p-347" id="p-347" id="p-347"

[00347]To a (R)-4-(6-chloro-4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)-3- methylmorpholine (150 mg, 0.49 mmol) and tert-butyl 5-amino-lH-pyrazole-l- carboxylate (116 mg, 0.59 mmol) in dioxane (8 mL) were added C82CO3 (400 mg, 1.23 mmol) and BrettPhos Pd G3 (45 mg, 0.049 mmol). The mixture was charged with N2 twice, then stirred at 90 °C overnight. The reaction was diluted with water and extracted with EtOAc (30 mLx2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Pre-TLC (DCM/MeOH=10/l) to afford the desired product (30 mg, yield 16.67 %). LC/MS (ESI) m/z: 369.1 [M+H]+.148 WO 2022/002245 PCT/CN2021/104232 id="p-348" id="p-348" id="p-348" id="p-348" id="p-348"

[00348]1H NMR (400 MHz, DMSO-d6) 5 ppm 11.68 (br s, 1 H) 8.80 (br s, 1 H) 6.(br s, 1 H) 6.05 (br s, 1 H) 5.98 (s, 1 H) 4.33 - 4.34 (m, 1 H) 4.29 (br d, 1=6.52 Hz, H)3.93(brdd, J=11.16, 3.01 Hz, 1 H) 3.82 - 3.88 (m, 1 H) 3.70 - 3.74 (m, 1H)3.61 - 3.65 (m, 1 H) 3.48 (td, 1=11.72, 2.82 Hz, 1 H) 3.06 (td, 1=12.68, 3.64 Hz, 1 H) 2.(s, 3 H) 2.25 (s, 3 H) 2.18 (s, 3 H) 1.15 (d, 1=6.64 Hz, 3 H).

Example 42 Biochemical Assays id="p-349" id="p-349" id="p-349" id="p-349" id="p-349"

[00349] Assay 1: ATR inhibition assay id="p-350" id="p-350" id="p-350" id="p-350" id="p-350"

[00350]Detection of ATR kinase activity utilized the Mobility shift assay to measure the phosphorylation of the substrate protein FAM-RAD 17 (GL, Cat. No. 514318, Lot. No. P19042-MJ524315). The assay was developed and conducted at Chempartner. All the test compounds were dissolved in 100% DMSO at concentration of 20 mM, then prepare compounds and conducted the assay as follows: 1) Transfer 80pl 20mM compound to 40pl of 100% DMSO in a 96-well plate. 2) Serially dilute the compound by transferring 20pl to 60pl of 100% DMSO in the next well and so forth for a total of 10 concentrations. 3) Add 100 pl of 100% DMSO to two empty wells for no compound control and no enzyme control in the same 96-well plate. Mark the plate as source plate. 4) Transfer 40 pl of compound from source plate to a new 384-well plate as the intermediate plate.

) Transfer 60 nl compounds to assay plate by Echo. 6) Add ATR kinase (Eurofins, Cat. No. 14-953, Lot. No. D14JP007N) into Kinase base buffer (50 mM HEPES, pH 7.5; 0.0015% Brij-35; 0.01% Triton) to prepare 2 x enzyme solution, then add 10 pl of 2x enzyme solution to each well of the 384-well assay plate, incubate at room temperature for 10 min. 149 WO 2022/002245 PCT/CN2021/104232 7) Add FAM-RAD 17 and ATP (Sigma, Cat. No. A7699-1G, CAS No. 987-65-5) in the kinase base buffer to prepare 2x peptide solution, then add lOpl to the assay plate. 8) Incubate at 28°C for specified period of time. Add 40 pl of stop buffer (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mMEDTA) to stop reaction. 9) Collect data on Caliper. Convert conversion values to inhibition values.

Percent inhibition = (max-conversion)/(max-min)*100 wherein "max" stands for DMSO control; "min" stands for low control.

Fit the data in XLFit excel add-in version 5.4.0.8 to obtain IC50 values. Equation used is: Y=Bottom + (Top-Bottom )/(l+(IC50/X)AHillSlope) wherein X means concentration in a format not transformed to logarithms. id="p-351" id="p-351" id="p-351" id="p-351" id="p-351"

[00351]The following Table 2 lists the IC50 values for exemplary compounds of Formula (I).

Table 2 Compound No. ATRIC50 (nM)14.416.318.5162813.2221013 150 WO 2022/002245 PCT/CN2021/104232 19 10.315.517.011.821.9915.730.433.312.32.519.752.739.3 id="p-352" id="p-352" id="p-352" id="p-352" id="p-352"

[00352] Assay 2: Tumor Cell Anti-proliferation Assay (CTG Assay) id="p-353" id="p-353" id="p-353" id="p-353" id="p-353"

[00353]Human colorectal cancer cells HT-29 (HTB-38) and L0V0 (CCL-229) were selected for the CTG assay, the two cell lines were originally obtained from the American Type Culture Collection (ATCC). Add FBS and appropriate additives into base medium to prepare complete medium, then briefly rinse the cell layer with 0.25% (w/v) Trypsin-0 038% (w/v) EDTA solution to remove all traces of serum that contains trypsin inhibitor, after that, add appropriate volume of Trypsin-EDTA solution to flask and observe cells under an inverted microscope until cell layer is dispersed, at last, add appropriate volume of complete growth medium and aspirate cells by gently pipetting. Collect and count numbers with Vi-cell XR and adjust cell density, seed cells into 96-well opaque-walled clear bottom tissue-culture treated plates in the CO2 incubator for 20-24 hours. All the test compounds will be at mM in DMSO. Compounds are then added to the cell media in 3-fold serial dilutions, the final DMSO concentration is 0.5%. Incubate plates for 96h at 5% CO2, 37°C. Before the measurement, transfer the appropriate volume of CellTiter-Glo Buffer into the amber bottle containing CellTiter-Glo substrate to reconstitute the lyophilized enzyme/substrate mixture, mix gently, this forms the CellTiter-Glo Reagent (Promega Cat. No. G7573). Equilibrate the plate and its contents to room 151 WO 2022/002245 PCT/CN2021/104232 temperature for approximately 30 minutes, then add 100 pL of CellTiter-Glo Reagent to the assay plate, mix contents for 2 minutes on an orbital shaker to induce cell lysis, incubate at room temperature for 10 minutes to stabilize luminescent signal, at last paste the clear bottom with white back seal and record luminescence with Enspire. IC50 and GI50 values were calculated with XLFit curve fitting software using Parameter Logistic Model Y=Bottom + (Top-Bottom)/(l+(IC50/X)AHillSlope). id="p-354" id="p-354" id="p-354" id="p-354" id="p-354"

[00354]The following Table 3 provides the IC50 (Y=50%) values for exemplary compounds of Formula (I).

Table 3 Compound No. L0V0 IC 50 (nM)334385653401872397.8538262.91307611807515594225192388428309517564 152 WO 2022/002245 PCT/CN2021/104232 28 4068424427189668004928446983706406533971012410390

Claims

WO 2022/002245 PCT/CN2021/104232 WHAT CLAIMED IS:

1. A compound having Formula (I): or a pharmaceutically acceptable salt thereof, wherein Ring Ais absent, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl; Visa direct bond, carbonyl or alkyl optionally substituted with one or more Rc; W and L are each independently a direct bond, -O-, -S-, or -N(Ra)-; R1 is alkyl, cyano, hydroxyl, -S(O)2CH3, or -S(O)(NH)CH3; R2 is hydrogen, halogen or alkyl optionally substituted with one or more Rb; R5/jH-J ZNRing Bis n ; R5 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and haloalkyl; Ra is hydrogen or alkyl; Rb is hydroxyl or halogen; Rc is hydroxyl, halogen or alkyl; n is 0, 1, 2, or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, whereinVisa direct bond. WO 2022/002245 PCT/CN2021/104232

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein V is carbonyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein V is alkyl optionally substituted with one or more Rc.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 3- to 6-membered cycloalkyl,

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopropyl, cyclopentyl or cyclohexyl, preferably

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered heterocyclyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl or tetrahydropyranyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered heteroaryl.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein Ring A is thiazolyl, triazolyl, pyridyl or isoxazolyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is absent.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is a direct bond.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is -N(Ra)-.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is absent, and W is -N(Ra)-.

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Ra is hydrogen or methyl. WO 2022/002245 PCT/CN2021/104232

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is absent, and W is a direct bond.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is alkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-3 alkyl.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is -S(O)2CH3 or -S(O)(NH)CH3.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is cyano or hydroxyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl or 5- to 6- membered heteroaryl, and R1 is alkyl, hydroxyl, -S(O)2CH3 or-S(O)(NH)CH3.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopropyl, cyclohexyl, tetrahydropyranyl, thiazolyl, triazolyl, pyridyl or isoxazolyl.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered heterocyclyl, and R1 is alkyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl, triazolyl or isoxazolyl, and R1 is C1-3 alkyl.

25. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl, triazolyl or isoxazolyl, and R1 is methyl.

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is absent, and R1 is cyano or -S(O)2CH3.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is -O-.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is -S-. WO 2022/002245 PCT/CN2021/104232

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is -N(Ra)-.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein Ra is hydrogen.

32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, whereinR5 ARing Bis N

33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 L is -O-, -S- or -N(Ra)-, and Ring Bis N .

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Ra is hydrogen.

35. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or alkyl.

36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

37. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is halogen.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R2 is fluoro.

39. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl substituted with one or more Rb.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-3 alkyl substituted with one or more Rb.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl substituted with one or more Rb.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Rb is hydroxyl or fluoro. WO 2022/002245 PCT/CN2021/104232

43. The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, having a Formula (II) or Formula (III): (n), (in).

44. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: (IVb), (IVc), WO 2022/002245 PCT/CN2021/104232 (IVd), (IVe), (IVf), and (IVg), wherein U is O or NH; Visa direct bond, carbonyl or alkyl optionally substituted with one or more Rc; W and L are each independently -O-, -S- or -N(Ra)-; R1 is alkyl; R2 is hydrogen, halogen, or alkyl substituted with one or more Rb; WO 2022/002245 PCT/CN2021/104232 R5 is hydrogen or alkyl; Ra is hydrogen or alkyl; Rb is hydroxyl or halogen; and Rc is hydroxyl, halogen or alkyl.

45. The compound of claim 1 selected from the group consisting of: WO 2022/002245 PCT/CN2021/104232 WO 2022/002245 PCT/CN2021/104232 or a pharmaceutically acceptable salt thereof.

46. A compound having Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein Ring Ais absent, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl; Q is a direct bond or alkyl optionally substituted with one or more Rd; WO 2022/002245 PCT/CN2021/104232 L is -O-, -S- or -N(Ra)-; RA Ring Bis M ; Ra is hydrogen or alkyl; Rd is hydroxyl, halogen or alkyl; R1 is selected from the group consisting of cyano, hydroxyl, halogen, -S(O)2CH3, and -S(O)(NH)CH3; R5 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and haloalkyl; n is 0, 1, 2, or 3.

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Q is a direct bond.

48. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Q is alkyl.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein Q is C1-3 alkyl.

50. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Ring A is 3- to 6-membered cycloalkyl

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopropyl.

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein Ring A is .

53. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Ring A is absent.

54. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered heterocyclyl. WO 2022/002245 PCT/CN2021/104232

55. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Ring A is tetrahydropyranyl.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein Ring A is o .

57. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Q is alkyl and Ring A is absent.

58. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Q is a direct bond and Ring A is 3- to 6-membered cycloalkyl or 5- to 6- membered heterocyclyl.

59. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R1 is -S(O)2CH3 or-S(O)(NH)CH3.

60. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, hydroxyl or halogen.

61. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Ring A is absent, 3- to 6-membered cycloalkyl or 5- to 6-membered heterocyclyl, and R1 is -S(O)2CH3 or-S(O)(NH)CH3.

62. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Ring A is absent or 3- to 6-membered cycloalkyl, and R1 is cyano, hydroxyl or halogen.

63. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein L is -O-.

64. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein L is -S-.

65. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein L is -N(Ra)- and Ra is hydrogen.

66. The compound of any one of claims 63-65, or a pharmaceutically acceptable salt thereof, wherein Ring B is R5 WO 2022/002245 PCT/CN2021/104232

67. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or alkyl.

68. The compound of claim 46 selected from the group consisting of: WO 2022/002245 PCT/CN2021/104232 or a pharmaceutically acceptable salt thereof.

69. A pharmaceutical composition comprising the compound of any one of claims 1- or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

70. A method for treating cancer, comprising administering an effective amount of a compound of any one of claims 1-68 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 69 to a subject in need thereof.

71. Use of the compound of any one of claims 1-68 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 69 in the manufacture of a medicament for treating cancer.

72. A compound of any one of claims 1-68 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 69, for use in the treatment of cancer.

73. A method for inhibiting ATR kinase in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1-68 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 69 to the subject.